Methods, apparatuses, and systems for the treatment of pulmonary disorders

ABSTRACT

Apparatuses, systems and methods are provided for treating pulmonary tissues via delivery of energy, generally characterized by high voltage pulses, to target tissue using a pulmonary tissue modification system (e.g., an energy delivery catheter system). Example pulmonary tissues include, without cells), lamina propria, submucosa, submucosal glands, basement membrane, smooth muscle, cartilage, nerves, pathogens resident near or within the tissue, or a combination of any of these. The system may be used to treat a variety of pulmonary diseases or disorders such as or associated with COPD (e.g., chronic bronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), acute bronchitis and/or other pulmonary diseases or disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. PatentApplication No. 62/355,164, filed Jun. 27, 2016, entitled “Methods,Apparatuses, and Systems for the Treatment of Pulmonary Disorders” andU.S. Patent Application No. 62/489,753, filed Apr. 25, 2017, entitled“methods, Apparatuses, and Systems for the Treatment of PulmonaryDisorders”. The disclosures of both of the foregoing applications areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION I. Anatomy

FIG. 1 provides an illustration of the pulmonary anatomy. Air travelsdown the trachea T and into the lungs L where the trachea T branchesinto a plurality of airways that extend throughout the lungs L. Thetrachea T first bifurcates into the right and left mainstem bronchi MBat the carina CA. These main bronchi MB further divide into the lobarbronchi LB, segmental bronchi SB, sub-segmental bronchi SSB, andterminate with the alveoli A. The diameters of the airways decrease asthey bifurcate. The trachea T can have a luminal diameter ranging fromabout 15 mm to 22 mm, the mainstem bronchi MB can have a luminaldiameter ranging from about 12 mm to 16 mm, the lobar bronchi LB can aluminal diameter ranging from about 9 mm to 12 mm, and the diameter ofsubsequent bronchi continue to become smaller. The length of the airwayalso varies with each segment. In some patients, the trachea T has alength of about 12 cm, the mainstem bronchi MB has a length of about 4.8cm, the lobar bronchi LB has a length of about 1.9 cm, and the length ofsubsequent bronchi continue to become shorter. In addition, the airwaywalls become thinner and have less supporting structure as they movemore distally into the lung tissue.

The airways of the lung L are comprised of various layers, each with oneor several types of cells. FIG. 2 illustrates a cross-sectional viewrepresentative of an airway wall W having a variety of layers andstructures. The inner-most cellular layer of the airway wall W is theepithelium or epithelial layer E which includes pseudostratifiedcolumnar epithelial cells PCEC, goblets cells GC and basal cells BC.Goblet cells GC are responsible for the secretion of mucus M, whichlines the inner wall of the airways forming a mucus blanket. Thepseudostratified columnar epithelial cells PCEC include cilia C whichextend into the mucus blanket. Cilia C that are attached to theepithelium E beat towards the nose and mouth, propelling mucus M up theairway in order for it to be expelled.

The basal cells BC attach to the basement membrane BM, and beneath thebasement membrane BM resides the submucosal layer or lamina propria LP.The lamina propria LP includes a variety of different types of cells andtissue, such as smooth muscle SM. Smooth muscle is responsible forbronchoconstriction and bronchodilation. The lamina propria LP alsoinclude submucosal glands SG. Submucosal glands SG are responsible formuch of the inflammatory response to pathogens and foreign material.Likewise, nerves N are present. Nerve branches of the vagus nerve arefound on the outside of the airway walls or travel within the airwaywalls and innervate the mucus glands and airway smooth muscle,connective tissue, and various cell types including fibroblasts,lymphocytes, mast cells, in addition to many others. And finally,beneath the lamina propria LP resides the cartilaginous layer CL.

FIG. 3 provides a cross-sectional illustration of the epithelium E of anairway wall W showing types of cellular connections within the airway.Pseudostratified columnar epithelial cells PCEC and goblet cells GC areconnected to each other by tight junctions TJ and adherens junctions AJ.The pseudostratified columnar epithelial cells PCEC and goblet cells GCare connected to the basal cells BC by desmosomes D. And, the basalcells BC are connected to the basement membrane BM by hemidesmosomes H.

II. Pulmonary Disorders

FIGS. 4A-4B depict bronchial airways B in healthy and diseased states,respectively. FIG. 4A illustrates a bronchial airway B in a healthystate wherein there is a normal amount of mucus M and no inflammation.FIG. 4B illustrates a bronchial airway B in a diseased state, such aschronic obstructive pulmonary disease, particularly chronic bronchitis.Chronic bronchitis is characterized by a persistent airflow obstruction,chronic cough, and sputum production for at least three months per yearfor two consecutive years. FIG. 4B illustrates both excess mucus M andinflammation I which leads to airway obstruction. The airwayinflammation I is consistent with a thickened epithelial layer E.

A variety of pulmonary disorders and diseases lead to airwayobstruction. A few of these disorders and diseases will be describedbriefly herein.

A. Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive Pulmonary Disease (COPD) is a common diseasecharacterized by chronic irreversible airflow obstruction and persistentinflammation as a result of noxious environmental stimuli, such acigarette smoke or other pollutants. COPD includes a range of diseaseswith chronic bronchitis primarily affecting the airways; whereas,emphysema affects the alveoli, the air sacs responsible for gasexchange. Some individuals have characteristics of both.

In chronic bronchitis, the airway structure and function is altered. Inchronic bronchitis, noxious stimuli such as cigarette smoke orpollutants are inhaled and recognized as foreign by the airways,initiating an inflammatory cascade. Neutrophils, lymphocytes,macrophages, cytokines and other markers of inflammation are found inthe airways of people with prolonged exposure, causing chronicinflammation and airway remodeling. Goblet cells can undergohyperplasia, in which the cells increase in number, or hypertrophy, inwhich the goblet cells increase in size. Overall, the goblet cellsproduce more mucus as a response to the inflammatory stimulus and toremove the inhaled toxins. The excess mucus causes further airwayluminal narrowing, leading to more obstruction. Cilia are damaged by thenoxious stimuli, and therefore the excess mucus remains in the airwaylumen, obstructing airflow from proximal to distal during inspiration,and from distal to proximal during the expiratory phase. Smooth musclecan become hypertrophic and thicker, causing bronchoconstriction.Submucosal glands can also become hyperplastic and hypertrophic,increasing the overall thickness of the airway wall and, which furtherconstricting the diameter of the lumen.

In addition to a reduction in the luminal diameter of the airway, mucushypersecretion can also lead to an exacerbation, or general worsening ofhealth. As a consequence of the excess mucus and damaged cilia,pathogens such as bacteria (e.g., Haemophilus influenzae, Streptococcuspneumoniae, Moraxella catarrhalis, Staphylococcus aureus, Pseudomonasaeruginosa, Burkholderia cepacia, opportunistic gram-negatives,Mycoplasma pneumoniae, and Chlamydia pneumoniae), viruses (rhinoviruses,influenze/parainfluenza viruses, respiratory syncytial virus,coronaviruses, herpes simplex virus, adenoviruses), and other organisms(e.g., fungi) can flourish, causing an exacerbation, resulting in a setof symptoms. These include worsening cough, congestion, an increase insputum quantity, a change in sputum quality, and/or shortness of breath.Treatment for an acute exacerbation can include oral or intravenoussteroids, antibiotics, oxygen, endotracheal intubation and the need formechanical ventilation via a ventilator.

B. Asthma

Asthma is a disease of the airways characterized by airwayhyper-responsiveness. In asthma, the epithelium can be thickened, mucushypersecretion can be present as a result of excess production fromgoblet cells and submucosal glands, and smooth muscle can be thickened.As discussed herein, mucus hypersecretion or excess mucus can allowpathogens to flourish, leading to an infection.

C. Interstitial Pulmonary Fibrosis

Interstitial pulmonary fibrosis is thought to be initiated with acuteinjury to the lung tissue that leads to chronic and aberrantinflammation. Fibroblasts are activated in response to the inflammation,which causes pulmonary fibrosis, scarring, and worsening lung function.Only 20 to 30% of patients are alive at five years after the diagnosis.

D. Cystic Fibrosis (CF)

Cystic Fibrosis (CF) is a systemic disease with pulmonary manifestationsdefined by a genetic defect, wherein the Cystic Fibrosis TransmembraneConductance Regulator (CFTR) gene is mutated, leading to thickenedsecretions that cannot be expelled. Chronic inflammation leads to airwayremodeling and hypersecretion via the goblet cells and submucosalglands, which lead to airway constriction and infections that aredifficult to full resolve.

D. Bronchiectasis

Bronchiectasis is a condition that leads to the airways to dilate,become thickened and scarred. It usually occurs due to an infection orother condition that injures the airway walls, prevents the airway fromclearing mucus, or both. With this condition, the airways lose theirability to clear mucus, which can lead to repeated infections. Eachinfection causes additional damage, eventually leading to moderateairflow obstruction. Bronchiectasis can be caused by genetic disorderssuch as primary ciliary dyskinesia or can be of idiopathic origin.

III. Pulmonary Treatments

In some instances, the most effective treatment for a pulmonary disorderis a lifestyle change, particularly smoking cessation. This isparticularly the case in COPD. However, many patients are unable orunwilling to cease smoking. A variety of treatments are currentlyavailable to reduce symptoms of pulmonary disorders.

A. Medication

COPD can be managed with one or several medications, such as ShortActing Beta Agonists (SABAs), Long Acting Beta Agonists (LABAs), LongActing Muscarinic Antagonists (LAMAs), steroids, chronic antibiotictherapy, or PDE4 inhibitors such as Roflumilast. SABAs and LABAs act onthe beta receptor of smooth muscle in the airway to causebronchodilation. LAMAs act via anticholinergic pathways, inhibiting therelease of acetylcholine causing bronchodilation. LABAs and LAMAs havebeen demonstrated to decrease breathlessness, reduce frequency ofexacerbations and improve quality of life but have not been shown todecrease mortality. Tiotropium, a LAMA, can slow the rate of decline oflung function and increase the time until an exacerbation. Inhaledcorticosteroids directly target inflammation. Inhaled corticosteroidshave been demonstrated to decrease exacerbations but have little effecton lung function and mortality. Combinations of LABAs, LAMAs and inhaledcorticosteroid drugs have been formulated. Inhaled oxygen is known todecrease breathlessness and improve mortality but these results are onlyassociated with advanced disease represented by strict criteria andrequire chronic administration via nasal cannula or alternativeapparatuses.

COPD can also be managed with one or several oral medications, such asPDE4 inhibitors, steroids, and antibiotics. Roflumilast is an oralmedication that is a selective long acting inhibitor of the enzyme PDE4.It has very strong anti-inflammatory effects but is not well tolerated,with adverse effects including diarrhea, weight loss, nausea, decreasedappetite and abdominal pain among others. Oral steroids such asprednisone can be prescribed to a patient in order to treat acuteinflammation during an exacerbation. Patients have been known tocontinue on oral steroids for long periods of time if withdrawal leadsto another exacerbation. Oral steroids have many side effects such asweight gain, insomnia, thyroid dysfunction, and osteoporosis, amongothers. Azithromycin or long term administration of antibiotics has beenshown to reduce the frequency of COPD exacerbations. Antibiotics canachieve this via an antimicrobial effect by killing the pathogensresponsible for the exacerbation or by other mechanisms such as areduction in mucus secretion as has been shown with macrolideantibiotics. Side effects of long-term administration of antibioticsinclude hearing loss and antibiotic resistance.

Oftentimes patients are non-compliant with prescribed respiratorymedications. Inhaled therapies require deep inspiration as well assynchronization with inspiration, which many patients, especially theelderly, cannot perform. Patients can skip doses secondary to cost,experience side effects, or both. Together, all of these factorscontribute to inadequate and inconsistent dosing.

Asthma can range in severity in adults, from mild disease to persistent.Milder disease can be adequately managed with trigger avoidance andShort Acting Beta Agonists (SABAs) whereas the mainstay of therapy forpersistent asthma is inhaled glucocorticoids. Regular use of inhaledglucocorticoids has been shown in clinical trials to reduce the need forrescue inhalers, improve lung function, decrease symptoms, and preventexacerbations. Some patients benefit from the addition of a leukotrienemodifying agent or LABA. Tiotropium can be another option to improvelung function, more so than inhaled glucocorticoids alone. Very severecases can require temporary or long term treatment with oralcorticosteroids.

There is no known cure for interstitial pulmonary fibrosis (IPF). Themainstay of treatment is supplemental oxygen when required andpreventive measures, such as vaccination. Pirfenidone is ananti-fibrotic agent that is approved for IPE, attempting to slow thefibroblast foci, collagen disposition and inflammatory cell infiltrationof the disease. In clinical trials, Pirfenidone has been shown to reducethe decline in vital capacity (a measure of pulmonary function) anddemonstrated a reduction in all-cause mortality. Nintedanib is anotheragent approved for IPF and acts via a receptor blocker for multipletyrosine kinases that mediate elaboration of fibrogenic growth factors(e.g., platelet-derived growth factor, vascular endothelial growthfactor, fibroblast growth factor). It appears to slow the rate ofdisease progression in IPF. No device therapy is approved for IPF.

Treatment for cystic fibrosis has rapidly evolved from chestphysiotherapy and supplemental oxygen to therapies that target theunderlying defect in the CFTR gene. Ivacaftor is a CFTR potentiator,improving the transport of chloride through the ion channel, which isFDA approved for several CFTR gene mutations. In clinical trials it hasbeen shown to improve FEV1 and reduce the frequency of exacerbations. Italso improves mucociliary and cough clearance. It does not, however,improve outcomes when used alone in patients with the most common deltaF508 deletion. Other targeted therapies are in clinical trials. Chronicantibiotics are commonly prescribed for CF, including azithromycin,which likely has anti-inflammatory benefits, and inhaled tobramycin totreat Pseudomonas aeruginosa. As with other obstructive diseases, CFpatients benefit from bronchodilators including LABAs and LAMAs. Agentsto promote airway secretion clearance include inhaled DNasc to decreasethe viscosity of mucus, inhaled hypertonic saline to draw water from theairway in the mucus, and inhaled N-acetylcysteine that cleaves disulfidebonds within mucus glycoproteins. Guidelines recommend against chronicuse of inhaled corticosteroids although oral steroids can be used incases of exacerbations.

Bronchiectasis is the anatomic manifestation of a host injury responseresulting in the excess dilatation of airway luminal caliber and thustherapy is often directed at the cause of the primary disease. These canbe non-tuberculous mycobacteria infection, primary immunodeficiencies,allergic bronchopulmonary and aspergillosis among others. Treatment ofacute exacerbation is focused on treating the offending bacterialpathogens with antibiotics. Macrolide and non-macrolide antibiotics havebeen shown to reduce the frequency of exacerbations. The use of inhaledantibiotics in the absence of CF is unclear as are the use of mucolyticagents. Bronchodilators can be used in patients with signs of airwayobstruction on spirometry.

Primary Ciliary Dyskinesia (PCD) interventions aim to improve secretionclearance and reduce respiratory infections with daily chestphysiotherapy and prompt treatment of respiratory infections. The roleof nebulized DNase and other mucolytic drugs is less clear.

Respiratory tract infections caused by pathogens in the airway can occurwith any of these maladies, and are typically treated with antibiotics.Unfortunately, drug development in this area is in decline and currenttherapies have significant limitations. One issue is that there is noone agent capable of treating the spectrum of pathogens found in thesepatients. While sputum testing can be performed to determine theresident pathogen or pathogens, this sometimes requires that specimensbe obtained by bronchoscopy with special techniques to avoid samplecontamination that typically effect other methods and modalities ofcollection. Another issue is that currently-available medicines are notalways effective, due to pathogens developing a resistance to thesetherapies.

B. Interventional Procedures

More recently, several groups have developed interventional proceduresfor COPD. Surgical Lung Volume Reduction (LVR) has been proven to be aneffective therapy, although the morbidity and mortality rates are highin this frail population. Bronchoscopic Lung Volume Reduction (BLVR) canbe achieved by the placement of one-way valves, coils, vapor steamablation, or by delivering biologic or polymer based tissue glues intotarget lobes. The physiologic target for LVR/BLVR is emphysema, whichspecifically addresses the hyperinflation that these patientsexperience. In several studies, BLVR has been demonstrated to improvepulmonary function and quality of life. Volume reducing therapies arenot effective in patients with chronic bronchitis, which is a disease ofthe airways, not the alveoli.

Another emerging therapy is lung denervation in which theparasympathetic nerves that innervate the airways are ablated,theoretically leading to chronic bronchodilation by disabling thereactive airway smooth muscle. The effect can be similar to thebronchodilator drugs like LABAs and LAMAs, but provide for long-termeffect without the typical peaks and troughs seen with medicationdosing. Due to only proximal treatment with this modality, it can belimited in effect to the upper airways whereas the higher resistanceairways are lower in the respiratory tract.

A variety of thermal ablation approaches have also been described astherapies to treat diseased airways, but all have limitations andchallenges associated with controlling the ablation and/or targetingspecific cell types. Spray cryotherapy is applied by spraying liquidnitrogen directly onto the bronchial wall with the intent of ablatingsuperficial airway cells and initiating a regenerative effect on thebronchial wall. Since the operator (e.g., physician) is essentially‘spray painting’ the wall, coverage, dose and/or depth of treatment canbe highly operator dependent without appropriate controllers. This canlead to incomplete treatment with skip areas that were not directlysprayed with nitrogen. Lack of exact depth control can also lead tounintended injury to tissues beyond the therapeutic target such aslamina propria and cartilage, especially since airway wall thickness canvary. Radiofrequency and microwave ablation techniques have also beendescribed wherein energy is delivered to the airway wall in a variety oflocations to ablate diseased tissue. Due to uncontrolled thermalconduction, an inability to measure actual tissue temperature to controlenergy delivery, risk of overlapping treatments, and variable wallthickness of the bronchi, these therapies can cause unintended injury totissues beyond the therapeutic target, as well. In addition, since theyall require repositioning of the catheter for multiple energyapplications, incomplete treatment can also occur. All of these thermalablative technologies non-selectively ablate various layers of theairway wall, often undesirably ablating non-target tissues beyond theepithelium. As a consequence of damage to tissues beyond the therapeutictargets of the epithelium, an inflammatory cascade can be triggered,resulting in inflammation, which can lead to an exacerbation, andremodeling. As a result, the airway lumen can be further reduced. Thus,continued improvements in interventional procedures are needed which aremore controlled, targeted to specific depths and structures that matchthe physiologic malady, while limiting the amount of inflammatoryresponse and remodeling.

Asthmatx has previously developed a radiofrequency ablation system toconduct Bronchial Thermosplasty. The operator deploys a catheter in theairways and activates the electrode, generating heat in the airwaytissue in order to thermally ablate smooth muscle. Because of the acuteinflammation associated with the heat generated in the procedure, manypatients experience acute exacerbations. In the AIR2 clinical study,patients did not experience a clinically significant improvement in theAsthma Quality of Life Questionnaire at 12 months as compared to a shamgroup. However, the treatment group had fewer exacerbations and adecrease in emergency room visits. The FDA approved the procedure, butit is not commonly used due to the side effects and the designation byinsurers as an investigational procedure.

There is hence an unmet need for interventional procedures which aremore controlled, targeted to specific structures and/or pathogens thatmatch the pathophysiologic aberrancy or aberrancies, able to treatrelatively large surface areas as the appropriate depth, and limit theamount of inflammatory response and remodeling. The present inventionmeets at least some of these objectives.

SUMMARY OF THE INVENTION

Described herein are embodiments of apparatuses, systems and methods fortreating or manipulating pulmonary tissues and/or treating pulmonarydiseases or disorders such as or associated with COPD (e.g., chronicbronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cysticfibrosis, bronchiectasis, primary ciliary dyskinesia (PCD), acutebronchitis and/or other pulmonary diseases or disorders, wherein one ormore features from any of these embodiments can be combined with one ormore features from one or more other embodiments to form a newembodiment within the scope of this disclosure. Example pulmonarytissues include, without limitation, the epithelium (the goblet cells,ciliated pseudostratified columnar epithelial cells, and basal cells),lamina propria, submucosa, submucosal glands, basement membrane, smoothmuscle, cartilage, nerves, pathogens resident near or within the tissue,or a combination of any or all of the foregoing.

The methods, apparatuses, and systems disclosed herein can treatpulmonary tissues via delivery of energy, generally characterized byhigh voltage pulses, to target tissue using a pulmonary tissuemodification system (e.g., an energy delivery catheter system). In someembodiments, the nature of the energy delivery allows for removal oftarget tissue without a clinically significant inflammatory healingresponse, while in other embodiments, some inflammatory healing responseis considered acceptable. This further allows for regeneration ofhealthy new target tissue within days of the procedure. In otherembodiments, the nature of the energy delivery allows for removal ofpathogens resident in the airway, such as by destruction, withoutsubstantially impacting or injuring any other airway structures.

In a first aspect, a system is provided for reducing hypersecretion ofmucus in a lung passageway of a patient, the system comprising, a) acatheter comprising at least one electrode disposed near its distal end,wherein the distal end of the catheter is configured to be positionedwithin a lung passageway so that the at least one electrode is able totransmit non-thermal energy to an airway wall of the lung passageway,and b) and a generator in electrical communication with the at least oneelectrode, wherein the generator includes at least one energy deliveryalgorithm configured to provide an electric signal of the non-thermalenergy transmittable to the airway wall which selectively treatsparticular cells associated with hypersecretion of mucus within theairway wall causing reduced hypersecretion of mucus by the airway wall.

In some embodiments, selectively treats comprises selectively removesthe particular cells from the airway wall. In some embodiments, removescomprises cell detachment. For example, cell detachment may be achievedby dielectrophoresis. In some embodiments, removes comprises cell death.For example, cell death may be achieved by electroporation. Or, celldeath may occur by other mechanisms. Likewise, removes may comprise acombination of dielectrophoresis and electroporation or othermechanisms.

In some embodiments, the particular cells comprise epithelial cells andnot basal cells. For example, the epithelial cells may comprise abnormalor hyperplastic goblet cells. Or, the epithelial cells may compriseabnormal ciliated pseudostratified columnar epithelial cells.

In some embodiments, the particular cells comprise cells of a basementmembrane, and wherein selectively treats comprises modifying the cellsof the basement membrane so as to modify the permeability of thebasement membrane. In some embodiments, the particular cells comprisesubmucosal glands, and wherein selectively treats comprises causing celldeath of the submucosal glands. In some embodiments, the particularcells comprise pathogens, and wherein selectively treats comprisescausing cell death of the pathogens. In some embodiments, selectivelytreats comprises selectively modifies the particular cells to altermucus production.

In some embodiments, the electric signal has a waveform comprising atleast one energy packet, wherein each energy packet comprises a seriesof pulses. In some instances, each pulse is between approximately 500 Vto 10 kV. In other instances, each pulse is between approximately500-4000 V.

In some embodiments, the at least one energy packet has a frequency inthe range of approximately 500-800 kHz. It may be appreciated that insome embodiments, each pulse is biphasic.

In some embodiments, the system further comprises a temperature sensordisposed along the catheter so as to contact the airway wall and monitortemperature at or in the airway wall. In some embodiments, the generatorincludes a processor in communication with the temperature sensor,wherein the processor modifies the at least one energy deliveryalgorithm if the temperature increases to or above a temperaturethreshold for thermal tissue effects.

In some embodiments, the system further comprises an impedance sensordisposed along the catheter so as to contact the airway wall and monitorimpedance within the airway wall, wherein the impedance sensorcommunicates with an indicator that indicates a condition of the airwaywall based on the impedance. In some instances, the condition of theairway will comprises completeness of treatment of the particular cells.In some instances, the condition of the airway wall comprises lack ofeffect of the treatment of the particular cells.

In some embodiments, the generator further comprises a mechanism foracquiring a cardiac signal of the patient and a processor configured toidentify a safe time period for transmitting the non-thermal energy tothe airway wall of the lung passageway based on the cardiac signal. Insome embodiments, the safe time period occurs during an ST segment ofthe cardiac signal. In other embodiments, the safe time period occursduring a QT interval of the cardiac signal.

In some embodiments, the system further comprises at least one sensorconfigured to sense a parameter of the airway wall, wherein thegenerator further comprises a processor configured to modify the atleast one energy delivery algorithm based on data from the at least onesensor so as to create a feedback loop.

In some embodiments, the catheter comprises at least two protrusionsexpandable to contact the airway wall of the lung passageway. In someembodiments, the at least two protrusions comprises a plurality of wiresforming an expandable basket, wherein at least one of wires acts as theat least one electrode. In some embodiments, the catheter includes ashaft and wherein the shaft does not pass through the expandable basket.In some embodiments, at least a portion of one of the plurality of wiresis insulated from a nearby wire of the plurality of wires. In someembodiments, the at least a portion of one of the plurality of wires isinsulated leaving an exposed portion of wise so as to create an activearea which concentrates the energy at a particular location along theairway wall of the lung passageway. In some embodiments, the pluralityof wires is simultaneously energizable. In other embodiments, at leastsome of the plurality of wires are individually energizable.

In some embodiments, the at least one electrode comprises a separateelectrode mounted on at least one of the at least two protrusions. Insuch embodiments, the separate electrode may have a coil shape.

In some embodiments, the catheter includes a shaft and wherein the atleast two profusions comprises a plurality of wires having one endattached to the shaft and one free end so as to form a half expandablebasket.

In some embodiments, the system further comprises a sheath advanceableover the catheter so as the collapse the at least two protrusions.

In a second aspect of the present invention, a system is provided forregenerating normative healthy tissue in an abnormally functioning lungpassageway of a patient, the system comprising, a) a catheter comprisingat least one electrode disposed near its distal end, wherein the distalend of the catheter is configured to be positioned within a lungpassageway so that the at least one electrode is able to transmitnon-thermal energy to an airway wall of the lung passageway, and b) agenerator in electrical communication with the at least one electrode,wherein the generator includes at least one energy delivery algorithmconfigured to provide an electric signal of the non-thermal energytransmittable to the airway wall which removes abnormally functioningcells from the airway wall while maintaining a collagen matrix structurewithin the airway wall so as to allow regeneration of the airway wallwith normative healthy tissue.

In some embodiments, removes comprises cell detachment. For example,cell detachment may be achieved by dielectrophoresis. In someembodiments, removes comprises cell death. For example, cell death maybe achieved by electroporation. Or, cell death may occur by othermechanisms. Likewise, removes may comprise a combination ofdielectrophoresis and electroporation or other mechanisms.

In some embodiments, the abnormally functioning cells compriseepithelial cells and not basal cells. In some instances, the epithelialcells comprise abnormal or hyperplastic goblet cells. In some instances,the epithelial cells comprise abnormal ciliated pseudostratifiedcolumnar epithelial cells. In some embodiments, the abnormallyfunctioning cells comprise submucosal glands, and wherein removescomprises causing cell death of the submucosal glands.

In some embodiments, the electric signal has a waveform comprising atleast one energy packet, wherein each energy packet comprises a seriesof pulses. In some instances, each pulse is between approximately 500 Vto 10 kV. In other instances, each pulse is between approximately500-4000 V. In some embodiments, the at least one energy packet has afrequency in the range of approximately 500-800 kHz. In someembodiments, each pulse is biphasic.

In some embodiments, the system further comprises a temperature sensordisposed along the catheter so as to contact the airway all and monitortemperature at or in the airway wall. In some embodiments, the generatorincludes a processor in communication with the temperature sensor,wherein the processor modifies the at least one energy deliveryalgorithm if the temperature increases to or above a temperaturethreshold for thermal tissue effects.

In some embodiments, the system further comprises an impedance sensordisposed along the energy catheter so as to contact the airway wall andmonitor impedance within the airway wall, wherein the impedance sensorcommunicates with an indicator that indicates a condition of the airwaywall based on the impedance.

In some embodiments, the condition of the airway wall comprises lack ofeffect of removal of abnormally functioning cells.

In some embodiments, the generator further comprises a mechanism foracquiring a cardiac signal of the patient and a processor configured toidentify a safe time period for transmitting the non-thermal energy tothe airway wall of the lung passageway based on the cardiac signal. Insome embodiments, the safe time period occurs during an ST segment ofthe cardiac signal. In some embodiments, the safe time period occursduring a QT interval of the cardia signal.

In some embodiments, the system further comprises at least one sensorconfigured to sense a parameter of the airway wall, wherein thegenerator further comprises a processor configured to modify the atleast one energy delivery algorithm based on data from the at least onesensor so as to create a feedback loop.

In some embodiments, the catheter comprises at least two protrusionsexpandable to contact the airway wall of the lung passageway. In someinstances, the at least two protrusions comprises a plurality of wiresforming an expandable basket, wherein at least one of wires acts as theat least one electrode.

In some embodiments, the catheter includes a shaft and wherein the shaftdoes not pass through the expandable basket.

In some embodiments, at least a portion of one of the plurality of wiresis insulated from a nearby wire of the plurality of wires. In someembodiments, the at least a portion of one of the plurality of wires isinsulated leaving an exposed portion of wire so as to create an activearea which concentrates the energy at a particular location along theairway wall of the lung passageway. In some embodiments, the pluralityof wires is simultaneously energizable. In other embodiments, at leastsome of the plurality of wires are individually energizable.

In some embodiments, the at least one electrode comprises a separateelectrode mounted on at least one of the at least two protrusions. Insuch instances, the separate electrode may have a coil shape.

In some embodiments, the catheter includes a shaft and wherein the atleast two protrusions comprises a plurality of wires having one endattached to the shaft and one free end so as to form a half expandablebasket.

In some embodiments, the system further comprises a sheath advanceableover the catheter so as the collapse the at least two protrusions.

In a third aspect of the present invention, a system is provided forregenerating normative healthy tissue in an abnormally functioning lungpassageway of a patient, the system comprising, a) a catheter comprisingat least one electrode disposed near its distal end, wherein the distalend of the catheter is configured to be positioned within a lungpassageway so that the energy delivery body is able to transmitnon-thermal energy to an airway wall of the lung passageway, and b) agenerator in electrical communication with the at least one electrode,wherein the generator includes at least one energy delivery algorithmconfigured to provide an electric signal of the non-thermal energytransmittable to the airway wall which removes cells from the airwaywall that are contributing to abnormal function of the lung passagewaywhile maintaining a collagen matrix structure within the airway wall soas to allow regeneration of the airway wall with normative healthytissue.

In some embodiments, removes comprises cell detachment. For example, theelectric signal may cause cell detachment by dielectrophoresis. In someembodiments, removes comprises cell death.

In some embodiments, the cells comprise epithelial cells and not basalcells. For instance, the epithelial cells may comprise abnormal orhyperplastic goblet cells. Or, the epithelial cells may compriseabnormal ciliated pseudostratified columnar epithelial cells.

In some embodiments, the cells comprise lymphocytes, macrophages,eosinophils, fibroblasts, plasma cells, mast cells, leukocytes or acombination of these. In some embodiments, the cells comprise submucosalglands, and wherein removes comprises causing cell death of thesubmucosal glands. In other embodiments, the cells comprise pathogens.

In some embodiments, the electric signal has a waveform comprising atleast one energy packet, wherein each energy packet comprises a seriesof pulses. For example, each pulse may be between approximately 500 V to10 kV. Or, each pulse may be between approximately 500-4000 V. In someembodiments, the at least one energy packet has a frequency in the rangeof approximately 500-800 kHz. In some embodiments, each pulse isbiphasic.

In some embodiments, the system further comprises a temperature sensordisposed along the catheter so as to contact the airway wall and monitortemperature at or in the airway wall.

In some embodiments, the generator includes a processor in communicationwith the temperature sensor, wherein the processor modifies the at leastone energy delivery algorithm if the temperature increases to or above atemperature threshold for thermal tissue effects.

In some embodiments, the system further comprises an impedance sensordisposed along the catheter so as to contact the airway wall and monitorimpedance within the airway wall, wherein the impedance sensorcommunicates with an indicator that indicates a condition of the airwaywall based on the impedance.

In some embodiments, the condition of the airway wall comprises lack ofeffect of removal of cells.

In some embodiments, the generator further comprises a mechanism foracquiring a cardiac signal of the patient and a processor configured toidentify a safe time period for transmitting the non-thermal energy tothe airway wall of the lung passageway based on the cardiac signal. Insome embodiments, the safe time period occurs during an ST segment ofthe cardiac signal. In some embodiments, the safe time period occursduring a QT interval of the cardiac signal.

In some embodiments, the system further comprising at least one sensorconfigured to sense a parameter of the airway wall, wherein thegenerator further comprises a processor configured to modify the atleast one energy delivery algorithm based on data from the at least onesensor so as to create a feedback loop.

In some embodiments, the catheter comprises at least two protrusionsexpandable to contact the airway wall of the lung passageway. In someembodiments, the at least two protrusions comprises a plurality of wiresforming an expandable basket, wherein at least one of wires acts as theat least one electrode.

In some embodiments, the catheter includes a shaft and wherein the shaftdoes not pass through the expandable basket.

In some embodiments, at least a portion of one of the plurality of wiresis insulated from a nearby wire of the plurality of wires. In someembodiments, the at least a portion of one of the plurality of wires isinsulated leaving an exposed portion of wire so as to create an activearea which concentrates the energy at a particular location along theairway wall of the lung passageway.

In some embodiments, the plurality of wires is simultaneouslyenergizable. In some embodiments, at least some of the plurality ofwires are individually energizable.

In some embodiments, the at least one electrode comprises a separateelectrode mounted on at least one of the at least two protrusions. Insuch embodiments, the separate electrode may have a coil shape.

In some embodiments, the catheter includes a shaft and wherein the atleast two protrusions comprises a plurality of wires having one endattached to the shaft and one free end so as to form a half expandablebasket.

In some embodiments, the system further comprises a sheath advanceableover the catheter so as the collapse the at least two protrusions.

In a fourth aspect of the present invention, a system is provided forremoving epithelial cells from a body passageway, the system comprising,a) a catheter comprising at least one electrode disposed near its distalend, wherein the distal end of the catheter is configured to bepositioned within the body passageway so that the at least one electrodeis able to transmit non-thermal energy to a wall of the body passageway,and b) a generator in electrical communication with the at least oneelectrode, wherein the generator includes at least one energy deliveryalgorithm configured to provide an electric signal of the non-thermalenergy transmittable to the airway wall which detaches epithelial cellsfrom the wall by dielectrophoresis so as to allow regeneration of thewall with normative healthy tissues.

In some embodiments, the epithelial cells comprise goblet cells. In someembodiments, the epithelial cells comprise ciliated pseudostratifiedcolumnar epithelial cells. In yet other embodiments, the epithelialcells comprise goblet cells and ciliated pseudostratified columnarepithelial cells but not basal cells.

In some embodiments, the body passageway comprises a lung passageway.For example, the body passageway may comprises a blood vessel, alymphatic vessel, a kidney tubule, an esophagus, a stomach, a smallintestine, a large intestine, a large intestine, an appendix, a rectum,a bladder, a ureter, a pharynx, a mouth, a vagina, a urethra, or a ductof a gland.

In some embodiments, the electric signal has a waveform comprising atleast one energy packet wherein each energy packet comprises a series ofpulses. In some embodiments, each pulse is between approximately 500 Vto 10 kV. In other embodiments, each pulse is between approximately500-4000 V. In some embodiments, the at least one energy packet has afrequency in the range of approximately 500-800 kHz. In someembodiments, each pulse is biphasic.

In some embodiments, the system further comprises a temperature sensordisposed along the catheter so as to contact the airway wall and monitortemperature at or in the airway wall. In some embodiments, the generatorincludes a processor in communication with the temperature sensor,wherein the processor modifies the at least one energy deliveryalgorithm if the temperature increases to or above a temperaturethreshold for thermal tissue effects.

In some embodiments, the system further comprises an impedance sensordisposed along the catheter so as to contact the airway wall and monitorimpedance within the airway wall, wherein the impedance sensorcommunicates with an indicator that indicates a condition of the airwaywall based on the impedance. In some embodiments, the condition of theairway wall comprises lack of effect of detachment of cells.

In some embodiments, the generator further comprises a mechanism foracquiring a cardiac signal of the patient and a processor configured toidentity a safe time period for transmitting the non-thermal energy tothe airway wall of the lung passageway based on the cardiac signal. Insome embodiments, the safe time period occurs during an ST segment ofthe cardiac signal. In some embodiments, the safe time period occursduring a QT interval of the cardiac signal.

In some embodiments, the system further comprises at least one sensorconfigured to sense a parameter of the airway wall, wherein thegenerator further comprises a processor configured to modify the atleast one energy delivery algorithm based on data from the at least onesensor so as to create a feedback loop.

In some embodiments, the catheter comprises at least two protrusionsexpandable to contact the airway wall of the lung passageway. In someembodiments, the at least two protrusions comprises a plurality of wiresforming an expandable basket, wherein at least one of wires acts as theat least one electrode. In some embodiments, the catheter includes ashaft and wherein the shaft does not pass through the expandable basket.In some embodiments, the at least a portion of one of the plurality ofwires is insulated from a nearby wire of the plurality of wires. In someembodiments, the at least a portion of one of the plurality of wires isinsulated leaving an exposed portion of wire so as to create an activearea winch concentrates the energy at a particular location along theairway wall of the lung passageway.

In some embodiments, the plurality of wires is simultaneouslyenergizable. In some embodiments, at least some of the plurality ofwires are individually energizable.

In some embodiments, the at least one electrode comprises a separateelectrode mounted on at least one of the at least two protrusions. Insuch instances, the separate electrode may have a coil shape.

In some embodiments, the catheter includes a shaft and wherein the atleast two protrusions comprises a plurality of wires having one endattached to the shaft and one free end so as to form a half expandablebasket.

In some embodiments, they system further comprises a sheath advanceableover the catheter so as the collapse the at least two protrusions.

In a fifth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast one energy delivery algorithm and a processor, wherein theprocessor which provides electrical signal of the energy according tothe at least one energy delivery algorithm, each electrical signalhaving a waveform comprising at least one energy packet, wherein eachenergy packet comprises a series of pulses, and wherein the energyselectively treats particular cells associated with hypersecretion ofmucus within the lung passageway causing reduced hypersecretion ofmucus.

In some embodiments, each pulse is between approximately 500-4000 volts.

In some embodiments, the energy is delivered in a monopolar fashion andeach pulse is between approximately 2000-3500 volts. In otherembodiments, the energy is delivered in a bipolar fashion and each pulseis between approximately 500-1900 volts.

In some embodiments, the particular cells comprise epithelial coils andnot basal cells.

In some embodiments, an increase in voltage of the pulses causes theenergy to selectively treat particular cells located more deeply withina wall of the lung passageway.

In some embodiments, the at least one energy packet has a frequency isin the range of approximately 500-800 kHz.

In some embodiments, the energy is below a threshold for treating acartilage layer within the lung passageway. In some embodiments, theenergy is below a threshold for causing thermal ablation.

In some embodiments, the system further comprises a temperature sensorconfigured to contact a wall of the lung passageway and monitortemperature at or in the wall.

In some embodiments, the processor is in communication with thetemperature sensor, and wherein the processor modifies the at least oneenergy delivery algorithm if the temperature increases to or above atemperature threshold for thermal tissue effects. In some embodiments,each pulse is biphasic.

In some embodiments, treats comprises removes the particular cells.

In some embodiments, the particular cells comprise cells of a basementmembrane, and wherein selectively treats comprises modifying the cellsof the basement membrane so as to modify the permeability of thebasement membrane.

In some embodiments, the particular cells comprise submucosal glands,and wherein selectively treats comprises causing cell death of thesubmucosal glands. In some embodiments, the particular cells comprisepathogens, and wherein selectively treats comprises causing cell deathof the pathogens.

In some embodiments, the system further comprises a cardiac monitorconfigured to acquire a cardiac signal of the patient, and wherein theprocessor provides the electrical signal of the energy insynchronization the cardiac signal.

In some embodiments, the processor provides the electrical signal ofenergy during an ST segment of the cardiac signal. In other embodiments,the processor provides the electrical signal of energy during a QTinterval of the cardiac signal.

In some embodiments, the system further comprises an impedance sensorconfigured to contact a wall of the lung passageway and monitorimpedance within the wall, wherein the impedance sensor communicateswith an indicator that indicates a condition of the wall based on theimpedance. In some embodiments, the condition of the airway wallcomprises completeness of treatment of the particular cells. In someembodiments, the condition of the airway wall comprises lack of effectof the treatment of the particular cells.

In some embodiments, the system further comprises at least one sensorconfigured to sense a parameter of a wall of the lung passageway,wherein the processor modifies the at least one energy deliveryalgorithm based on data from the at least one sensor so as to create afeedback loop.

In a sixth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast one energy delivery algorithm and a processor, wherein theprocessor provides an electrical signal of the energy according to theat least one energy delivery algorithm and wherein the energyselectively treats particular cells associated with hypersecretion ofmucus within the lung passageway causing reduced hypersecretion ofmucus, and b) at least one sensor in communication with the processor,wherein the sensor senses a condition of the lung passageway and theprocessor modifies at least one parameter of the at least one energydelivery algorithm based an the condition.

In some embodiments, the at least one parameter includes a voltage,frequency, packet duration, cycle count, number of energy packets, restperiod or dead time.

In some embodiments, the at least one sensor comprises a temperaturesensor and the condition comprises a temperature of a portion of a wallof the lung passageway.

In some embodiments, the at least one parameter includes a voltage, andwherein the processor seduces the voltage if the temperature reaches atemperature threshold.

In some embodiments, the processor ceases providing the electricalsignal of energy it the temperature reaches a temperature threshold.

In some embodiments, the system further comprises the catheter, whereinthe catheter includes at least one electrode positionable near oragainst a wall of the lung passageway so as to transmit the energy tothe lung passageway, wherein the at least one sensor comprises atemperature sensor and the condition comprises a temperature of the atleast one electrode.

In some embodiments, the at least one sensor comprises an impedancesensor and the condition comprises an impedance of a portion of a wallof the lung passageway. In some embodiments, the processor compares theimpedance to an impedance threshold and causes the generator to providean alert if the impedance is above the impedance threshold.

In some embodiments, the system further comprises the catheter, whereinthe catheter includes at least one electrode positionable near oragainst a wall of the lung passageway so as to transmit the energy tothe lung passageway, and wherein the alert comprises an indication thatat least one of the at least one electrodes is not properly positioned.

In some embodiments, the at least one parameter includes a voltage, andwherein the processor reduces the voltage if the impedance reaches animpedance threshold.

In some embodiments, the processor ceases providing the electricalsignal of energy if the impedance reaches an impedance threshold. Insome embodiments, the at least one sensor comprises a temperaturesensor, and impedance sensor, a surface conductance sensor, a membranepotential sensor, a capacitance sensor, a force sensor, or a pressuresensor.

In some embodiments, the system further comprises a cardiac monitorconfigured to acquire a cardiac signal of the patient, and wherein theprocessor provides the electrical signal of the energy insynchronization with the cardiac signal. In some embodiments, thecondition of the lung passageway comprises completeness of treatment ofthe particular cells. In some embodiments, the condition of the lungpassageway comprises lack of effect of the treatment of the particularcells.

In a seventh aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast two energy delivery algorithms and a processor, wherein theprocessor selects one of the at least two energy delivery algorithms andprovides an electrical signal of the energy according to the one of theat least two energy delivery algorithms and wherein the energyselectively treats particular cells associated with hypersecretion ofmucus within the lung passageway causing reduced hypersecretion ofmucus, and b) at least one sensor in communication with the processor,wherein the sensor senses a condition of the lung passageway and theprocessor selects a different one of the at least two energy deliveryalgorithms and provides an electrical signal of the energy according tothe different one of the at least two energy delivery algorithms.

In some embodiments, the at least one sensor comprises a temperaturesensor and the condition comprises a temperature of a portion of a wallof the lung passageway.

In some embodiments, the system further comprises the catheter, whereinthe catheter includes a least one electrode positionable near or againsta wall of the lung passageway so as to transmit the energy to the lungpassageway, wherein the at least one sensor comprises a temperaturesensor and the condition comprises a temperature of the at least oneelectrode.

In some embodiments, the at least one sensor comprises an impedancesensor and the condition comprises an impedance of a portion of a wallof the lung passageway. In some embodiments, the processor compares theimpedance to an impedance threshold and causes the generator to providean alert if the impedance is above the impedance threshold. In someembodiments, the at least one parameter includes a voltage, and whereinthe processor reduces the voltage if the impedance reaches an impedancethreshold.

In some embodiments, the at least one sensor comprises a temperaturesensor, and impedance sensor, a surface conductance sensor, a membranepotential sensor, a capacitance sensor, a force sensor, or a pressuresensor.

In some embodiments, the system further comprises a cardiac monitorconfigured to acquire a cardiac signal of the patient, and wherein theprocessor provides the electrical signal of the energy insynchronization with the cardiac signal. In some embodiments, thecondition of the lung passageway comprises completeness of treatment ofthe particular cells. In some embodiments, the condition of the lungpassageway comprises lack of effect of the treatment of the particularcells.

In an eighth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, as a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast one energy delivery algorithm and a processor, wherein theprocessor provides an electrical signal of the energy according to theat least one energy delivery algorithm and wherein the energy removesabnormally functioning cells from the airway wall, and b) at least onesensor in communication with the processor, wherein the sensor senses acondition of the lung passageway and the processor modifies at least oneparameter of the at least one energy delivery algorithm based on thecondition.

In ninth aspect of the present invention, a system is provided fortreating lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast one energy delivery algorithm and a processor, wherein theprocessor provides an electrical signal of the energy according to theat least one energy delivery algorithm and wherein the energy removescells from the airway wall that are contributing to abnormal function ofthe lung passageway while maintaining a collagen matrix structure withinthe airway wall so as to allow regeneration of the airway wall withnormative healthy tissue, and b) at least one sensor in communicationwith the processor, wherein the sensor senses a condition of the lungpassageway and the processor modifies at least one parameter of the atleast one energy delivery algorithm based on the condition.

In a tenth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast one energy delivery algorithm and a processor, wherein theprocessor provides an electrical signal of the energy according to theat least one energy delivery algorithm and wherein the energy detachesepithelial cells from the wall by dielectrophoresis so as to allowregeneration of the wall with normative healthy tissue, and b) at leastone sensor in communication with the processor, wherein the sensorsenses a condition of the lung passageway and the processor modifies atleast one parameter of the at least one energy delivery algorithm basedon the condition.

In an eleventh aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast two energy delivery algorithms and a processor, wherein theprocessor selects one of the at least two energy delivery algorithms andprovides an electrical signal of the energy according to the one of theat least two energy delivery algorithms and wherein the energy removesabnormally functioning cells from the airway wall, and b) at least onesensor in communication with the processor, wherein the sensor senses acondition of the lung passageway and the processor selects a differentone of the at least two energy delivery algorithms and provides anelectrical signal of the energy according to the different one of the atleast two energy delivery algorithms.

In a twelfth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a generatorconfigured to provide energy to a catheter which is configured to thepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast two energy delivery algorithms and a processor, wherein theprocessor selects one of the at least two energy delivery algorithms andprovides an electrical signal of the energy according to the one of theat least two energy delivery algorithms and wherein the energy removescells from the airway wall that are contributing to abnormal function ofthe lung passageway while maintaining a collagen matrix structure withthe airway wall so as to allow regeneration of the airway wall withnormative healthy tissue, and b) at least one sensor in communicationwith the processor, wherein the sensor senses a condition of the lungpassageway and the processor selects a different one of the at least twoenergy delivery algorithms and provides an electrical signal of theenergy according to the different one of the at least two energydelivery algorithms.

In a thirteenth aspect of the present invention, a system is providedfor treating a lung passageway of a patient comprising a) a generatorconfigured to provide energy to a catheter which is configured to bepositioned within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator includes atleast two energy delivery algorithms and a processor, wherein theprocessor selects one of the at least two energy delivery algorithms andprovides an electrical signal of the energy according to the one of theat least two energy delivery algorithms and wherein the energy detachesepithelial cells from the wall by dielectrophoresis so as to allowregeneration of the wall with normative healthy tissue, and b) at leastone sensor in communication with the processor, wherein the sensorsenses a condition of the lung passageway and the processor selects adifferent one of the at least two energy delivery algorithms andprovides an electrical signal of the energy according to the differentone of the at least two energy delivery algorithms.

In a fourteenth aspect of the present invention, a system is providedfor treating a lung passageway of a patient comprising, a) a catheterhaving at least one electrode positionable near or against a wall of thelung passageway so as to transmit energy to the lung passageway, b) atleast one sensor disposed along the catheter so as to senses a conditionof the lung passageway to generate a condition value, and c) a generatorhaving a processor configured to provide an alert if the sensor value toabove a threshold.

In some embodiments, the at least on sensor comprises an impedancesensor and the condition value comprises an impedance of a portion of awall of the lung passageway.

In some embodiments, the alert comprises an indication that at least oneof the at least one electrodes is not properly positioned. In someembodiments, the alert comprises an indication that at least one of theat least one electrodes is defective.

In a fifteenth aspect of the present invention, a system is provided fortreating a lung passageway of a patient comprising, a) a cardiac monitorconfigured to acquire a cardiac signal of the patient, b) a generatorwhich provides an electrical signal of energy to at least one electrodewhich is positionable within the lung passageway so that the energy istransmittable to the lung passageway, wherein the generator provides theelectrical signal in synchronization with the cardiac signal.

In some embodiments, the cardiac monitor is configured to send a cardiacsync pulse to the generator at a pre-determined point in the cardiacsignal, and wherein the generator provides the electrical signal ofenergy after a pre-determined delay from receiving the cardiac syncpulse. In some embodiments, the pre-determined point is a peak of an Rwave of the cardiac signal. In some embodiments, the pre-determineddelay is in the range of 50-100 milliseconds.

In some embodiments, the generator includes a processor which monitors aplurality of cardiac sync pulses, calculates a time interval betweensuccessive cardiac sync pulse and prevents the generator from providingthe electric signal if the time interval is not consistent for apre-determined number of cardiac sync pulses. In some embodiments, thepre-determined number of cardia sync pulses is five. In otherembodiments, the pre-determined number of cardiac sync pulses is three.In some embodiments, the processor reduces the pre-determined numbercardiac sync pulses if the generator has prior been prevented fromproviding the electric signal. In some embodiments, the generator isconfigured to send the electrical signal during an ST segment of thecardiac signal. In some embodiments, the generator is configured to sendthe electrical signal during a QT interval of the cardia signal. In someembodiments, the generator is configured to not send the electricalsignal during a T wave of the cardiac signal. In some embodiments, thegenerator is configured to not send the electrical signal during ablanking period. In some embodiments, the blanking period is 100-200milliseconds after an R wave peak of the cardiac signal.

In some embodiments, the system further comprises a catheter upon whichthe at least one electrode is mounted.

In some embodiments, the system further comprises an imaging modalityconfigured to image the lung passageway. In some embodiments, theimaging modality comprises a bronchoscope.

In a sixteenth aspect of the present invention, a system is provided forreducing hypersecretion of mucus in a lung passageway of a patient, thesystem comprising, a) a catheter comprising an energy delivery bodydisposed near its distal end, wherein the energy delivery body comprisesat least two protrusions expandable to contact a wall of the lungpassageway, wherein each protrusion includes at least one electrode; andb) a generator which provides an electrical signal to the at least oneelectrode which transmits non-thermal energy toward the wall in anenergy does, wherein the energy dose selectively treats particular cellsassociated with hypersecretion of mucus within the airway wall causingreduced hypersecretion of mucus by the airway wall.

In some embodiments, the at least two protrusions comprises a pluralityof wires forming an expandable basket, wherein at least one of wiresacts as the at least one electrode.

In some embodiments, the catheter includes a shaft and wherein the shaftdoes not pass through the expandable basket.

In some embodiments, the at least a portion of one of the plurality ofwires is insulated from a nearby wire of the plurality of wires. In someembodiments, the at least a portion of one of the plurality of wires isinsulated leaving an exposed portion of wire so as to create an activearea which concentrates the energy dose at a particular location alongthe wall of the lung passageway.

In some embodiments, the plurality of wires is simultaneouslyenergizable. In some embodiments, at least some of the plurality ofwires are individually energizable.

In some embodiments, the at least one electrode comprises a separateelectrode mounted on the at least two protrusions. In some embodiments,the separate electrode may have a coil shape.

In some embodiments, the catheter includes a shaft and wherein the atleast two protrusions comprises a plurality of wires having one endattached to the shaft and one free end so as to form a half expandablebasket.

In some embodiments, the system further comprises a sheath advanceableover the catheter so as the collapse the at least two protrusions.

In some embodiments, selectively treats comprises selectively removesthe particular cells from the airway wall. The particular cells maycomprise epithelial cells and not basal cells. In some instances, theepithelial cells comprise abnormal or hyperplastic goblet cells. Inother instances, the epithelial cells comprise abnormal ciliatedpseudostratified columnar epithelial cells.

In some embodiments, removes comprises cell detachment. In someembodiments, removes comprises cell death.

In some embodiments, the particular cells comprise cells of a basementmembrane, and wherein selectively treats comprises modifying the cellsof the basement membrane so as to modify the permeability of thebasement membrane.

In some embodiments, the particular cells comprise submucosal glands,and wherein selectively treats comprises causing cell death of thesubmucosal glands.

In some embodiments, the particular cells comprise pathogens, andwherein selectively treats comprises causing cell death of thepathogens.

In some embodiments, selectively treats comprises selectively modifiesthe particular cells to alter mucus production.

In some embodiments, the electric signal has a waveform comprising atleast one energy packet, wherein each energy packet comprises a seriesof pulses. In some embodiments, each pulse is between approximately 500V to 10 kV.

In some embodiments, the system further comprises a temperature sensordisposed along the energy delivery body so as to contact the airway walland monitor temperature at or in the airway wall.

In some embodiments, the generator includes a processor in communicationwith the temperature sensor, wherein the processor modifies the at leastone energy delivery algorithm if the temperature increases to or above atemperature threshold for thermal tissue effects.

In some embodiments, the system further comprises an impedance sensordisposed along the energy delivery body so as to contact the airway walland monitor impedance within the airway wall, wherein the impedancesensor communicates with an indicator that indicates a condition of theairway wall based on the impedance.

In some embodiments, the generator further comprises a mechanism foracquiring a cardiac signal of the patient and a processor configured toanalyze the cardiac signal and identify a safe time period fortransmitting the non-thermal energy to the airway wall of the lungpassageway.

In some embodiments, the system further comprises at least one sensorconfigured to sense a parameter of the airway wall, wherein thegenerator further comprises a processor configured to modify theelective signal based on data from the at least one sensor so as tocreate a feedback loop.

In a seventeenth aspect of the present invention, a method is providedfor reducing hypersecretion of mucus in a lung passageway of a patientcomprising, a) positioning at least one electrode within the lungpassageway so that the at least one electrode is disposed near oragainst a portion of an airway wall of the lung passageway, and b)energizing the at least one electrode so as to deliver non-thermalenergy to the portion of the airway wall, wherein the non-thermal energyselectively treats particular cells within the portion of the airwaywall, associated with hypersecretion of mucus causing reducedhypersecretion of mucus by the lung passageway.

In some embodiments, selectively treat comprises selectively removes theparticular cells from the airway wall. In some instances, the particularcells comprise epithelial cells and not basal cells. In some instances,the epithelial cells comprise abnormal or hyperplastic goblet cells. Inother instances, the epithelial cells comprise abnormal ciliatedpseudostratified columnar epithelial cells.

In some embodiments, removes comprises cell detachment. For example,removes may comprise cell detachment by dielectrophoresis. In someembodiments, removes comprises cell death.

In some embodiments, the particular cells comprise cells of a basementmembrane, and wherein selectively treats composes modifying the cells ofthe basement membrane so as to modify the permeability of the basementmembrane.

In some embodiments, the particular cells comprise submucosal glands,and wherein selectively treats comprises causing cell death of thesubmucosal glands.

In yet other embodiments, the particular cells comprise pathogens, andwherein selectively treats comprises causing cell death of thepathogens.

In some embodiments, selectively treats comprises selectively modifiesthe particular cells to alter mucus production.

In some embodiments, the at least one electrode comprises a plurality ofwires forming an expandable basket, and wherein positioning the at leastone electrode within the lung passageway composes expanding theexpandable basket so that at least one of the plurality of wirescontacts the airway wall of the lung passageway. In some embodiments,the plurality of wires acts as a monopolar electrode, and the methodfurther comprises positioning a return electrode near the patient. Insome embodiments, the plurality of wires acts as a bipolar electrode.

In some embodiments, the at least one electrode comprises at least twoelectrodes, and wherein energizing comprises energizing the at least twoelectrodes to act as a bipolar pair.

In some embodiments, the non-thermal energy has an energy dose, and themethod further comprises re-energizing the at least one electrode so asto deliver non-thermal energy having a different energy dose.

In some embodiments, the re-energizing step is in response to a sensedcondition of the portion or the airway wall. In some embodiments, thesensed condition comprises a temperature. In other embodiments, thesensed condition comprises an impedance.

In some embodiments, the method further comprises re-energizing the atleast one electrode so as to selectively treat different cells withinthe portion of the airway wall. In some embodiments, the particularcells comprise epithelial cells and the different cells comprisesubmucosal cells.

In some embodiments, energizing the at least one electrode comprisesenergizing the at least one electrode in synchronization with a cardiaccycle of the patient. In some embodiments, in synchronization comprisesoutside of a T wave of the cardiac cycle.

In some embodiments, the method further comprises re-positioning the atleast one electrode within the lung passageway so that the at least oneelectrode is disposed near or against a different portion of the airwaywall of the lung passageway, and energizing the at least one electrodeso as to deliver energy to the different portion of the airway wall. Insome embodiments, the portion and the different portion are adjacent toeach other.

In some embodiments, the method further comprises positioning the atleast one electrode within a different long passageway of the patient sothat the at least on e electrode is disposed near or against a portionof an airway wall of the different lung passageway, and energizing theat least one electrode so as to deliver energy to the portion of anairway wall of the different lung passageway.

In some embodiments, the non-thermal energy is provided by an electricalsignal having a waveform comprising at least one energy packet, whereineach energy packet comprises a series of pulses. In some embodiments,each pulse is between approximately 500-4000 volts. In some embodiments,each energy packet has a frequency in the range of approximately 500-800kHz.

These and other embodiments are described in further detail in thefollowing description related to the appended drawing figures.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned is thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 provides an illustration of the pulmonary anatomy.

FIG. 2 illustrates a cross-sectional view representative of an airwaywall having a variety of layers and structures.

FIG. 3 provides a cross-sectional illustration of the epithelium of anairway wall showing types of cellular connection within the airway.

FIG. 4A-4B depict bronchial airways in healthy and diseased states,respectively.

FIG. 5 illustrates an embodiment of a pulmonary tissue modificationsystem used in treatment of a patient.

FIG. 6 provides a closer view of the embodiment of the therapeuticenergy delivery catheter illustrated in FIG. 5.

FIG. 7 is a schematic illustration of an embodiment of a pulmonarytissue modification system.

FIG. 8A-8B illustrate a bronchoscope inserted in the mouth/oral cavityof the patient and the nose/nasal cavity of the patient, respectively.

FIG. 9, 10, 11 illustrate positioning of the distal end of the catheterinto the mainstem bronchi for treatment of the airway.

FIG. 12 is a flowchart illustrating methods described herein in astep-wise approach to treating patients.

FIG. 13 illustrates an embodiment of a waveform of a signal provided byan energy delivery algorithm.

FIG. 14 illustrates an example waveform of another energy deliveryalgorithm.

FIG. 15 illustrates an example waveform of another energy deliveryalgorithm.

FIG. 16 illustrates an example waveform of another energy deliveryalgorithm.

FIG. 17 illustrates at embodiment wherein delivered energy causes cellsto be removed by detachment of the cells from the airway wall.

FIG. 18 illustrates an embodiment wherein delivered energy causes cellsdie, ultimately removing the cells from the airway wall.

FIG. 19 schematically illustrates removal of epithelial cells by adielectrophoresis effect.

FIG. 20 is a graph illustrating portions of a sample electrocardiogram(ECG) trace of a human heart highlighting periods wherein it is desiredto deliver energy pulses to the lung passageway via the energy deliverybody.

FIG. 21 is a flowchart depicting an embodiment of a method forsynchronizing the delivery of energy with the cardiac cycle.

FIG. 22 illustrates accessing lung tissue, such as parenchyma, via thenose or mouth.

FIG. 23A-23B depict example images of lung passageways obtainable usingconfocal laser endomicroscopy (CLE) and optical coherence tomography(OCT), respectively.

FIG. 24 depicts an embodiment of an energy delivery catheter having asingle energy delivery body comprised of an electrode formed by aplurality of ribbons or wires forming a spiral-shaped basket.

FIG. 25 an embodiment wherein the energy delivery catheter includes twoenergy delivery bodies.

FIG. 26 depicts an embodiment of an energy delivery catheter having asingle energy delivery body comprised, wherein the energy delivery bodyis mounted on a shaft which extends through the energy delivery body.

FIG. 27 illustrates an embodiment wherein both energy delivery bodiesare carried on a single shaft.

FIG. 28A illustrates an embodiment wherein one energy delivery bodyenergy is unconstrained at one end forming a half basket shape whenexpanded.

FIG. 28B illustrates an embodiment wherein both the energy deliverybodies are comprised of braided metal wires configured to formhalf-baskets when expanded.

FIG. 29 illustrates a braided wire basket energy delivery body comprisedof energizable wires wherein some of the wires are insulated withportions of the insulation removed to define an active area.

FIG. 30 illustrates another embodiment wherein a tube is laser cut toform a collapsed basket with both ends constrained via the tube itself.

FIG. 31 illustrates an embodiment of an energy delivery body comprisedof wires which are insulated and one or more separate additionalelectrodes (shown as coils) are connected to the insulated basket wiresto form active areas.

FIG. 32 illustrates an embodiment of an energy delivery body comprisinga plurality of times.

FIG. 33 illustrates an embodiment of an energy delivery body comprisingone or more protrusions.

FIG. 34 illustrates an embodiment of energy delivery body comprising oneof more protrusions wherein each protrusion is formed from anon-conductive material and carries, supports, and/or is otherwisecoupled to a separate electrode.

FIG. 35 illustrates an embodiment of a catheter having two energydelivery bodies, each energy delivery body having the shape of anexpandable coil.

FIG. 36 illustrates an embodiment of an energy delivery body comprisinga coil having a width and a length, wherein the length of the coil ispre-shaped into a substantially circular pattern.

FIG. 37 illustrates an embodiment of an energy delivery body comprisinga rod having electrodes, wherein the length of the rod is pre-shapedinto a substantially circular pattern.

FIG. 38 illustrates an embodiment of a catheter having a sheathwithdrawn proximally thus exposing one or more prongs.

FIG. 38A is a cross-sectional illustration across A-A of FIG. 38.

FIG. 39 illustrates an embodiment of a prong having two electrodesattached to an insulating substrate therebetween as a means to maintaindistance between the electrodes.

FIG. 40 illustrates an embodiment if a prong having a narrowerinsulating substrate than depicted in FIG. 36.

FIG. 41 illustrates an embodiment of a prong having yet narrowerinsulating substrates and greater than two electrodes.

FIG. 42 illustrates a plurality of electrodes mounted on an insulatingsubstrate.

FIG. 43 illustrates the insulating substrate with electrodes as shown inFIGS. 36-37 configured as a helix.

FIG. 44 illustrates the insulating substrate with electrodes as shown inFIG. 38 configured as a helix.

FIG. 45A-45B illustrates expanding an expandable member until a desiredinterface between the prongs and bronchial wall is achieved.

FIG. 46 illustrates an embodiment of an energy delivery catheter withfour energy delivery bodies activatable in a bipolar/multiplexedfashion.

FIG. 47 illustrates monopolar energy delivery by supplying energybetween the energy delivery bodies and a dispersive (return) electrodeapplied externally to the skin of the patient.

FIG. 48 illustrates an example catheter removably connected to abronchoscope.

FIG. 49A-49C illustrate introduction of a catheter having two energydelivery bodies through a bronchoscope.

FIG. 50 is a schematic illustration of a single target segment within amainstem bronchi of a lung.

FIG. 51 is a schematic illustration of two target segments positionedadjacent to each other such that the overall target or treatment zone isgenerally contiguous.

FIG. 52 is a schematic illustration of two target zones within apatient.

FIG. 53 is a schematic side view illustration of a portion of an energydelivery body comprised of a braided basket.

FIG. 54 is a schematic cross-sectional view of the energy delivery bodyof FIG. 50 positioned within a lung passageway having an airway wall.

FIG. 55 is a schematic illustration of the effect of continuous fullcircumference treatment of an airway along a length of the energydelivery body.

FIG. 56 is a schematic illustration of a discontinuous tissue effect ina lung passageway.

FIG. 57A-57B illustrate histology example (Lab 6, Animal 1-10085); FIG.57A illustrates a section from an untreated airway, FIG. 57B illustratesa section from treated airway.

FIG. 58A-58B illustrate another histology example (Lab 6, Animal1-10085); FIG. 58A illustrates a section of an untreated airway, FIG.58B illustrates a section of a treated airway.

DETAILED DESCRIPTION OF THE INVENTION

Specific embodiments of the disclosed device, delivery system, andmethods will now be described with reference to the drawings. Nothing inthis detailed description is intended to imply that any particularcomponent, feature, or step is essential to the invention.

I. Overview

The secretion of mucus in the bronchial airways is an inherent part ofthe defense of the lungs, protecting the interior membranes andassisting in fighting off infections. The amount of mucus secretionvaries with a range of stimuli, including bacteria, particles andchemical irritants. Normal secretion levels rise and fall depending onthe transient conditions of the environment. Mucus on the epitheliallayer of the bronchial airways traps particles and the ciliated cellspermits moving of the mucus out of the lower airways so that it canultimately be cleared by coughing or swallowing. Mucus also containsantibacterial agents to aid in its defense function. Pathogens andharmless inhaled proteins are thus removed from the respiratory tractand have a limited encounter with other immune components. In thebronchial airways, mucus is produced by goblet cells. Goblet cellsproduce mucins that are complexed with water in secretory granules andare released into the airway lumen. In the large airways, mucus is alsoproduced by mucus glands. After infection or toxic exposure, the airwayepithelium upregulates its mucus secretory ability to cause coughing andrelease of sputum. Subsequently, the airway epithelium recovers andreturns to its normal state, goblet cells disappear, and coughingabates.

However, in some instances, such as in the development of many pulmonarydisorders and diseases, the body does not recover, chronically producingtoo much mucus and causing it to accumulate in the lungs. This createssymptoms such as chronic coughing, difficulty breathing, fatigue andchest pain or discomfort. Such hypersecretion of mucus occurs in manydisease states and is a major clinical and pathological feature incystic fibrosis (CF) related bronchiectasis, non-CF bronchiectasis,chronic obstructive pulmonary disease and asthma, to name a few.

These disorders are all associated with an impaired innate lung defenseand considerable activation of the host inflammatory response. Abnormallevels of antimicrobial peptides, surfactant, salivary lysozyme, sputumsecretory leukocyte protease inhibitor, and macrophages in addition tosignaling of toll-like receptors (TLRs), trigger pathways for mucintranscription and NF-KB (nuclear factor kappa-light-chain-enhancer ofactivated B cells). The increased mucus production and decreasedclearance causes increased exacerbations and airway epithelial injury.Ciliary activity is disrupted and mucin production is upregulated. Thereis expansion of the goblet cell population. Epithelial cellproliferation with differentiation into goblet cells increases.Likewise, inflammation is elevated during exacerbations which activatesproteases, destroying the elastic fibers that allow air and CO₂ to flowin and out of alveoli. IN response to injury, the airway epitheliumproduces even more mucus, which cannot be cleared. This primes theairways for another exacerbation cycle. As exacerbation cycles continue,the excessive mucus production leads to a pathological state withincreased risk of infection, hospitalization and morbidity.

To interrupt or prevent the cycle of disease progression, the airwaysare treated with a pulmonary tissue modification system useful forimpacting one or more cellular structures in the airway wall such thatthe airway wall structures are restored from a diseased/remodeled stateto a relatively normal state of architecture, function and/or activity.The pulmonary tissue modification system treats pulmonary tissues viadelivery of energy, generally characterized by high voltage pulses. Insome embodiments, the energy delivery allows for modification or removalof target tissue without a clinically significant inflammatory response,while in other embodiments, some inflammatory response is permissible.This allows for regeneration of healthy new tissue within days of theprocedure.

In one method, the energy output from the pulmonary tissue modificationsystem induces a separation in the epithelial layer E in which abnormaland dysfunctional ciliated pseudostratified columnar epithelial cellsPCEC and hyperplastic and abnormal goblet cells GC are separated fromthe basal cells BC and pulled into the airway lumen, where they areexpelled from the lumen of the airway. As a result, the basal cells BCare left on the basement membrane BM to regenerate normal goblet cellsGC and normal ciliated pseudostratified columnar epithelial cells PCEC,thereby inducing reverse remodeling of the disease to reduce the mucushypersecretion. The newly regenerated goblet cells GC are significantlyless productive of mucus and the newly regenerated ciliatedpseudostratified columnar epithelial cells PCEC regrown normallyfunctioning cilia C, which more easily expel mucus M. The reduction inmucus volume is felt directly by the patient, whose cough and airwayobstruction are reduced. Over the ensuing weeks, this translates into areduction in exacerbations and an improved quality of life.

In some embodiments, the energy induces epithelial separation betweenthe basal cells BC and more superficial goblet GC and ciliatedpseudostratified columnar epithelial cells PCEC because of the relativestrength of the cell-cell connections. The basal cells BC are connectedto the basement membrane BM by hemidesmosomes H (illustrated in FIG. 3)whereas the basal cells BC connect to the goblet cells GC and ciliatedpseudostratified columnar epithelial cells PCEC via desmosomes D(illustrated in FIG. 3). The energy parameters and electrodeconfigurations of the pulmonary tissue modification system can bedesigned such that the desmosomes connections D separate but thehemidesmosomes H remain intact, thereby removing the surface cells,leaving the basal cells BC substantially intact, and ready to regenerateepithelium. The regenerative process is faster than would normally occurin trauma or with a thermal ablative modality where the basementmembrane BM is disrupted and necrosis ensues. Basement membranedisruption and necrosis, such as in thermal ablation procedures, cancause activation of inflammatory pathways including T cells,macrophages, IL-13, IL-4, monocytes, proteases, cytokines, andchemokines among others. With methods disclosed herein, there is nosubstantial disruption of the basement membrane BM, and little or noacute inflammation. This allows for regeneration of healthy new targettissue within days of the procedure. It may be appreciated that in otherembodiments the energy output from the pulmonary tissue modificationsystem may induce other or additional changes to the airway wall W,leading to regeneration of healthy target tissue.

FIG. 5 illustrates an embodiment of a pulmonary tissue modificationsystem 100 used in treatment of a patient P. In this embodiment, thesystem 100 comprises a therapeutic energy delivery catheter 102connectable to a generator 104. The catheter 102 comprises an elongateshaft 106 having at least one energy delivery body 108 near its distalend and a handle 110 at its proximal end. Connection of the catheter 102to the generator 104 provides electrical energy to the energy deliverybody 108, among other features. The catheter 102 is insertable into thebronchial passageways of the patient P by a variety of methods, such asthrough a lumen in a bronchoscope 112, as illustrated in FIG. 5.

FIG. 6 provides a closer view of the embodiment of the therapeuticenergy delivery catheter 102 illustrated in FIG. 5. In this embodiment,the energy delivery body 108 comprises a single monopolar deliveryelectrode, however it may be appreciated that other types, numbers andarrangements may be used, further examples of which will be providedherein. In this embodiment, the energy delivery body 108 is comprised ofa plurality of wires or ribbons 120 constrained by a proximal endconstraint 122 and a distal end constraint 124 forming a spiral-shapedbasket serving as an electrode. In an alternative embodiment, the wiresor ribbons are straight instead of formed into a spiral-shape (i.e.,configured to form a straight-shaped basket). In still anotherembodiment, the energy delivery body 108 is laser cut from a tube. Insome embodiments, the energy delivery body 108 is self-expandable anddelivered to a targeted area in a collapsed configuration. Thiscollapsed configuration can be achieved, for example, by placing asheath 126 over the energy delivery body 108. In FIG. 6, a the cathetershaft 106 (within the sheath 126) terminates at the proximal endconstraint 122, leaving the distal end constraint 124 essentiallyunconstrained and free to move relative to the shaft 106 of the catheter102. Advancing the sheath 126 over the energy delivery body 108 allowsthe distal end constraint 124 to move forward, therebylengthening/collapsing and constraining the energy delivery body 108.

The catheter 102 includes a handle 110 at its proximal end. In someembodiments, the handle 110 is removable, such as by pressing a handleremoval button 130. In this embodiment, the handle 110 includes anenergy delivery body manipulation knob 132 wherein movement of the knob132 causes expansion or retraction/collapse of the basket-shapedelectrode. In this example, the handle 110 also includes a bronchoscopeworking port snap 134 for connection with the bronchoscope 112 and acable plug-in port 136 for connection with the generator 104.

Referring back to FIG. 5, in this embodiment, the therapeutic energydelivery catheter 102 is connectable with the generator 104 along with adispersive (return) electrode 140 applied externally to the skin of thepatient P. Thus, in this embodiment, monopolar energy delivery isachieved by supplying energy between the energy delivery body 108disposed near the distal end of the catheter 102 and the returnelectrode 140. It may be appreciated that bipolar energy delivery andother arrangements may alternatively be used, as will be described infurther detail herein. In this embodiment, the generator 104 includes auser interface 150, one or more energy delivery algorithms 152, aprocessor 154, a data storage/retrieval unit 156 (such as a memoryand/or database), and an energy-storage sub-system 158 which generatesand stores the energy to be delivered. In some embodiments, one or morecapacitors are used for energy storage/delivery, but as new technologyis developed any suitable element may be used. In addition, one or morecommunication ports are included.

It may be appreciated that in some embodiments, the generator 104 iscomprised of three sub-systems: 1) a high energy storage system, 2) ahigh voltage, medium frequency switching amplifier, and 3) the systemcontrol, firmware, and user interface. The system controller includes acardiac synchronization trigger monitor that allows for synchronizingthe pulsed energy output to the patient's cardiac rhythm. The generatortakes in AC (alternating current) mains to power multiple DC (directcurrent) power supplies. The generator's controller instructs the DCpower supplies to charge a high-energy capacitor storage bank beforeenergy delivery is initiated. At the initiation of therapeutic energydelivery, the generator's controller, high-energy storage banks and abi-phasic pulse amplifier operate simultaneously to create ahigh-voltage, medium frequency output.

The processor 154 can be, for example, a general-purpose processor, afield programmable gate array (FPGA), an application specific integratedcircuit (ASIC), a digital signal processor (DSP), and/or the like. Theprocessor 154 can be configured to run and/or execute applicationprocesses and/or other modules, processes and/or functions associatedwith the system 100, and/or a network associated with the system 100.

As used herein the term “module” refers to any assembly and/or set ofoperatively-coupled electrical components that can include, for example,a memory, a processor, electrical trances, optical connectors, software(executing in hardware), and/or the like. For example, a module executedin the processor can be any combination of hardware-based module (e.g.,a FPGA, and ASIC, a DSP) and/or software-based module (e.g., a module ofcomputer code stored in memory and/or executed at the processor) capableof performing one or more specific functions associated with thatmodule.

The data storage/retrieval unit 156 can be, for example, a random accessmemory (RAM), a memory buffer, a hard drive, a database, an erasableprogrammable read-only memory (EPROM), an electrically erasableread-only memory (EEPROM), a read-only memory (ROM), flash memory,and/or so forth. The data storage/retrieval unit 156 can storeinstructions to cause the processor 154 to execute modules, processesand/or functions associated with the system 100.

Some embodiments the data storage/retrieval unit 156 comprises acomputer storage product with a non-transitory computer-readable medium(also can be referred to as a non-transitory processor-readable medium)having instructions or computer code thereon for performing variouscomputer-implemented operations. The computer-readable medium (orprocessor-readable medium) is non-transitory in the sense that it doesnot include transitory propagating signals per se (e.g., a propagatingelectromagnetic wave carrying information on a transmission medium suchas space or a cable). The media and computer code (also can be referredto as code) can be those designed and constructed for the specificpurpose or purposes. Examples of non-transitory computer-readable mediainclude, but are not limited to: magnetic storage media such as harddisks, floppy disks, and magnetic tape; optical storage media such asCompact Disc/Digital Video Discs (CD/DVDs, Compact Disc-Read OnlyMemories (CD-ROMs), and holographic devices; magneto-optical storagemedia such as optical disks; carrier wave signal processing modules; andhardware devices that are specially configured to store and executeprogram code, such as ASICs, Programmable Logic Devices (PLDs),Read-Only Memory (ROM) and Random-Access Memory (RAM) devices. Otherembodiments described herein relate to a computer program product, whichcan include, for example, the instructions and/or computer codediscussed herein.

Examples of computer code include, but are not limited to, micro code ormicro-instructions, machine instructions, such as produced by acompiler, code used to produce a web service, and files containinghigher-level instructions that are executed by a computer using aninterpreter. For example, embodiments can be implemented usingimperative programming languages (e.g., C, Fortran, etc.) functionalprogramming languages (Haskell, Erlang, etc.), logical programminglanguages (e.g., Prolog), object-oriented programming languages (e.g.,Java, C++, etc.) or other suitable programming languages and/ordevelopment tools. Additional examples of computer code include, but arenot limited to, control signals, encrypted code, and compressed code.

In some embodiments, the system 100 can be communicably coupled to anetwork, which can be any type of network such as, for example, a localarea network (LAN), a wide area network (WAN), a virtual network, atelecommunications network, a data network, and/or the internet,implemented as a wired network and/or a wireless network. In someembodiments, any or all communications can be secured using any suitabletype and/or method of secure communication (e.g., secure sockets layer(SSL)) and/or encryption. In other embodiments, any or allcommunications can be unsecured.

The user interface 150 can include a touch screen and/or moretraditional buttons to allow for the operator to enter patient data,select a treatment algorithm (i.e. energy delivery algorithm 152),initiate energy delivery, view records stored on the storage/retrievalunit 156, or otherwise communicate with the generator 104.

Any of the systems disclosed herein can include a user interface 150configured to allow operator-defined inputs. The operator-defined inputscan include duration of energy delivery or other timing aspects of theenergy delivery pulse, power, target temperature, mode of operation, ora combination thereof. For example, various modes of operation caninclude system initiation and self-test, operator input, algorithmselection, pre-treatment system status and feedback, energy delivery,post energy delivery display or feedback, treatment data review and/ordownload, software update, or a combination thereof.

In some embodiments, the system 100 also includes a mechanism foracquiring an electrocardiogram (ECG), such as an external cardiacmonitor 170. Example cardiac monitors are available from AccuSyncMedical Research Corporation. In some embodiments, the external cardiacmonitor 170 is operatively connected to the generator 104. Here, thecardiac monitor 170 is used to continuously acquire the ECG. Externalelectrodes 172 may be applied to the patient P and to acquire the ECG.The generator 104 analyzes one or more cardiac cycles and identifies thebeginning of a time period where it is safe to apply energy to thepatient P, thus providing the ability to synchronize energy deliverywith the cardiac cycle. In some embodiments, this time period is withinmilliseconds of the R wave to avoid induction of an arrhythmia which mayoccur if the energy pulse is delivered on a T wave. It may beappreciated that such cardiac synchronization is typically utilized whenusing monopolar energy delivery, however it may be utilized in otherinstances.

In some embodiments, the processor 154, among other activities, modifiesand/or switches between the energy-delivery algorithms, monitors theenergy delivery and any sensor data, and reacts to monitored data via afeedback loop. It may be appreciated that in some embodiments theprocessor 154 is configured to execute one or more algorithms forrunning a feedback control loop based on one or more measured systemparameters (e.g., current), one or more measured tissue parameters(e.g., impedance), and/or a combination thereof.

The data storage/retrieval unit 156 stores data related to thetreatments delivered and can optionally be downloaded by connecting adevice (e.g., a laptop or thump drive) to a communication port. In someembodiments, the device has local software used to direct the downloadof information, such as, for example, instructions stored on the datastorage/retrieval unit 156 and executable by the processor 154. In someembodiments, the user interface 150 allows for the operator to select todownload data to a device and/or system such as, but not limited to, acomputer device, a tablet, a mobile device, a server, a workstation, acloud computing apparatus/system, and/or the like. The communicationports, which can permit wired and/or wireless connectivity, can allowfor data download, as just described but also for data upload such asuploading a custom algorithm or providing a software update.

As described herein, a variety of energy delivery algorithms 152 areprogrammable, or can be pre-programmed, into the generator 104, such asstored in memory or data storage/retrieval unit 156. Alternatively,energy delivery algorithms can be added into the data storage/retrievalunit to be executed by processor 154. Each of these algorithms 152 maybe executed by the processor 154. Examples algorithms will be describedin detail herein below. In some embodiments, the catheter 102 includesone or more sensors 160 that can be used to determine temperature,impedance, resistance, capacitance, conductivity, permittivity, and/orconductance, to name a few. Sensor data can be used to plan the therapy,monitor the therapy and/or provide direct feedback via the processor154, which can then alter the energy-delivery algorithm 152. Forexample, impedance measurements can be used to determine not only theinitial dose to be applied but can also be used to determine the needfor further treatment, or not.

It may be appreciated that any of the systems disclosed herein caninclude an automated treatment delivery algorithm that could dynamicallyrespond and adjust and/or terminate treatment in response to inputs suchas temperature, impedance, treatment duration or other timing aspects ofthe energy delivery pulse, treatment power and/or system status.

In some embodiments, imaging is achieved with the use of acommercially-available system, such as a bronchoscope 112 connected witha separate imaging screen 180, as illustrated in FIG. 5. It may beappreciated that imaging modalities can be incorporated into thecatheter 102 or used alongside or in conjunction with the catheter 102.The imaging modality can be mechanically, operatively, and/orcommunicatively coupled to the catheter 102 using any suitablemechanism.

FIG. 7 is a schematic illustration of an embodiment of a pulmonarytissue modification system 100. In this embodiment, the catheter 102 isconfigured for monopolar energy delivery. As shown, a dispersive(neutral) or return electrode 140 is operatively connected to thegenerator 104 while affixed to the patient's skin to provide a returnpath for the energy delivered via the catheter 102. The energy-deliverycatheter 102 includes one or more energy delivery bodies 108 (comprisedof electrode(s)), one or more sensors 160, (one or more imagingmodalities 162, one or more buttons 164, and/or positioning mechanisms166 (e.g., such as, but not limited to, levers and/or dials on a handlewith pull wires, telescoping tubes, a sheath, and/or the like) the oneor more energy delivery bodies 108 into contact with the tissue. In someembodiments, a foot switch 168 is operatively connected to the generator104 and used to initiate energy delivery.

As mentioned previously, the user interface 150 can include a touchscreen and/or more traditional buttons to allow for the operator toenter patient data, select a treatment algorithm 152, initiate energydelivery, view records stored on the storage/retrieval unit 156, orotherwise communicate with the generator 104. The processor 154 managesand executes the energy-delivery algorithm, monitors the energy deliveryand any sensor data, and reacts to monitored via a feedback loop. Thedata storage/retrieval unit 156 stores data related to the treatmentsdelivered and can be downloaded by connecting a device (e.g., a laptopor thumb drive) to a communication port 167.

The catheter 102 is operatively connected to the generator 104 and/or aseparate imaging screen 180. Imaging modalities 162 can be incorporatedinto the catheter 102 or used alongside or in conjunction with thecatheter 102. Alternatively or in addition, a separate imaging modalityor apparatus 169 can be used, such as a commercially-available system(e.g., a bronchoscope). The separate imaging apparatus 169 can bemechanically, operatively, and/or communicatively coupled to thecatheter 102 using any suitable mechanism.

Referring to FIG. 8A, a bronchoscope 112 is inserted in the mouth ororal cavity OC of the patient P. It may be appreciated that methods foraccessing the airway can include use of other natural orifices such asthe nose or nasal cavity NC (illustrated in FIG. 8B). Alternatively, asuitable artificial orifice may be used (not shown e.g., stoma,tracheotomy). Use of the bronchoscope 112 allows for directvisualization of the target tissues and the working channel of thebronchoscope 112 can be used to deliver the catheter 102 as per theapparatuses and systems disclosed herein, allowing for visualconfirmation of catheter placement and deployment. FIGS. 8A-8Billustrate advancement of the distal end of the catheter 102 into thetrachea T and the mainstem bronchi MB, though it may be appreciated thatthe catheter 102 may be advanced into the lobar bronchi LB, more distalsegmental bronchi SB and sub-segmental bronchi SSB if desired.

FIGS. 9-11 illustrate positioning of the distal end of the catheter 102into the mainstem bronchi MB for treatment of the airway. In someembodiments, the catheter 102 has an atraumatic tip 125 to allowadvancement through the airways without damaging or the airway walls W.FIG. 9 illustrates the catheter 102 advanced into the mainstem bronchiMB while the sheath 126 is covering the energy delivery body 108.Positioning of the catheter 102 may be assisted by various imagingtechniques. For example, the bronchoscope 112 may be used to providereal-time direct visual guidance to the target site and may be used toobserve accurate positioning of the catheter 102 before, during andafter the delivery of treatment. FIG. 10 illustrates withdrawal of thesheath 126, exposing the energy delivery body 108. It may be appreciatedthat in some embodiments, the energy delivery body 108 is self-expandingso that the sheath 126 holds the energy delivery body 108 in a collapsedconfiguration. In such embodiments, withdrawal of the sheath 126releases the energy delivery body 108, allowing self-expansion. In otherembodiments, the energy delivery body 108 is expanded by othermechanisms, such as movements of the knob 132, which may occur after thesheath 126 is withdrawn. FIG. 11 illustrates the basket-shaped energydelivery body 108 in an expanded configuration, wherein the energydeliver body 108 contacts the airway walls W. Additional imaging ca beused to verify positioning and/or make additional measurements (e.g.,depth).

Once the energy delivery body 108 is desirably positioned, treatmentenergy is provided to the airway wall W by the energy delivery body 108.The treatment energy is applied according to at least one energydelivery algorithm.

In some embodiments, the user interface 150 on the generator 104 is usedto select the desired treatment algorithm 152. In other embodiments, thealgorithm 152 is automatically selected by the generator 104 based uponinformation obtained by one or more sensors on the catheter 102, whichwill be described in more detail in later sections. A variety of energydelivery algorithms may be used. In some embodiments, the algorithm 152generates a signal having a waveform comprising a series of energypackets with rest periods between each packet, wherein each energypacket comprises a series of high voltage pulses. In some embodiments,each high voltage pulse is between about 500 V to 10 kV, or about 500 Vto about 5,000 V, including all values and subranges in between. In someembodiments, the energy provided is within the frequency range of about10 kHz to about 10 MHz, or about 100 kHz to about 1 MHz, including allvalues and subranges in between. The algorithm 152 delivers energy tothe walls of the airway so as to provide the desired treatment withminimal or not tissue heating. In some embodiments, a temperature sensoris used to measure electrode and/or tissue temperature during treatmentto ensure that energy deposited in the tissue does not result in anyclinically significant tissue heating. For example, a temperature sensorcan monitor the temperature of the tissue and/or electrode, and if apre-defined threshold temperature is exceeded (e.g., 65° C.), thegenerator can alter the algorithm to automatically cease energy deliveryor modify the algorithm to reduce temperature to below the pre-setthreshold. For example, if the temperature exceeds 65° C., the generatorcan reduce the pulse width or increase the time between pulses and/orpackets in an effort to reduce the temperature. This can occur in apre-defined step-wise approach, as a percentage of the parameter, or byother methods.

Conventional radiofrequency ablation (RFA) kills cells by application ofhigh frequency alternating current in the 350-550 kHz range, generatingheat in the tissue to product thermal necrosis of the cells. Many RFAdevices have been developed to treat cardiac arrhythmias, solid tumors,renal nerves, and others. Microwave ablation is another thermal ablationmodality in which 300 MHz to 300 GHz alternating current is used, alsoleading to thermal necrosis. This energy source is employed to targetsolid tumors because of the large ablation zones and uniform heating. Ingeneral, heat-related thermal ablation denatures the proteins within thetissue, causes a significant inflammatory response and can be difficultto control, often leading to injury to a non-target tissues. For certaintypes of treatments (e.g., tumor treatments), inflammation isacceptable, but when focused within the pulmonary airways, substantiveinflammation can lead to serious complications (e.g., exacerbation).While the denaturation of proteins along may or may not produce clinicalmorbidity, more intact, less denatured proteins allow for theopportunity to enhance the host response to various challenges to theimmune system, whether that is to affect pathogens, tumor, etc. Theselimitations especially make heat-related thermal ablation in the airwaysless desirable.

In contrast, the algorithm 152 prescribes energy delivery to the airwaywalls W which is non-thermal, thereby reducing or avoiding inflammation.In some embodiments, the algorithm 152 is tailored to affect tissue to apre-determined depth and/or to target specific types of cells within theairway wall. In some embodiments, the generator has several fixedalgorithm settings whereby the targeted cell depth is reflected in eachsetting. For instance, one setting/algorithm may primarily affect thepathogens resident in the mucus layer, another setting/algorithm maytarget the epithelium, another setting/algorithm may primarily targetthe epithelium, basement membrane, submucosa and/or smooth muscle, whileyet another setting/algorithm may primarily target the epithelium,basement membrane, submucosa, smooth muscle, submucosal glands and/ornerves. In some embodiments, treatment is performed at the samelocation, but in others, the operator may choose to affect certain celltypes at different locations. The setting utilized by the operator maybe dependent on the physiologic nature of the patient's condition.

The biological mechanisms and cellular processes by which the energyremoves the cells will be described in more detail in later sections.The energy treats the airway wall W at the target location in a mannerwhich allows the regeneration of healthy tissue. For example, normalgoblet cells GC and normal ciliated pseudostratified columnar epithelialcells PCEC are able to regenerate, thereby inducing reverse remodelingof the disease to reduce the mucus hypersecretion. The newly regeneratedgoblet cells GC are significantly less productive of mucus and the newlyregenerated ciliated pseudostratified columnar epithelial cells PCECregrow normally functioning cilia C, which more easily expel mucus M.Thus, healthy new target tissue can be regenerated within days of theprocedure. This dramatically reduces symptoms of cough and mucushypersecretion in patients which results in fewer and less severeexacerbations and improvement in quality of life.

FIG. 12 is a flowchart illustrating methods described herein in astep-wise approach to treating patients, wherein the methods areexecuted by a practitioner, therapeutic energy-delivery catheter, orgenerator as appropriate. In some embodiments, one or more of the stepsdisclosed herein can be optional. The first series of steps can be usedto assess patient anatomy and/or suitability for the procedure to decidewhether or not to treat. In some embodiments, this assessment can beoptional, but can include one or more of the following steps. First,gain access 300 to the airway (if needed). Second, perform any suitablepre-procedural imaging, sputum sampling and/or biopsies that can benecessary and/or desired 301. Pre-procedural imaging can include anon-invasive CT scan, bronchoscopy, confocal laser endomicroscopy (CLE),optical coherence tomography (OCT) or any other appropriate techniquealong with any measurements that can be taken (e.g., depth). Sputumsampling can include nasal mucosa brushing, nasal washing, bronchialbrushing, bronchial washing, and/or bronchoalveolar lavage. Then, decidewhether or not to treat the patient. If the decision is ‘No’ 302, go toEND 322. If the decision is ‘Yes’ 303, gain access, if needed 304. Insome embodiments, the treatment can be performed one or more days afterthe pre-procedure assessment. In this embodiment, it would be requiredto gain access 304.

In some embodiments, the treatment can be performed immediately afterthe pre-procedure assessment. In this embodiment, it may not benecessary to gain access again. In this embodiment, the next step 305 ofthe procedure is to deliver the catheter. As described above, thecatheter can be delivered by various methods, however for the ofproviding an example, the catheter is delivered via a working channel ofa bronchoscope. In the next step 306, the catheter is positioned at atarget site. Again, as an example, the bronchoscope can be used toprovide real-time direct visual guidance to the target site and be usedto observe accurate positioning of the catheter. This can includeplacement of one or more energy delivery bodies into contact with theairway wall. Additional imaging 307 can then be used to verifypositioning and/or make additional measurements (e.g., depth). At thenext step 308, the operator can optionally select the desired energydelivery algorithm 152. As described in detail above, this can includefor example, selecting an algorithm based on target depth of treatment.Alternatively, the generator is configured to apply a pre-definedalgorithm suitable for most patients. In this embodiment, the next step309 is to execute or apply the energy delivery algorithm. This can beaccomplished via a foot pedal or other mechanism described herein. Afterthe energy is applied, the operator can assess the energy application310. This can include performing additional imaging with or withoutmeasurements and/or reacting to messages communicated by the generator(e.g., an error with the energy delivery that can have led to incompletetreatment). If the treatment is not acceptable 311, then operator wouldgo back to the Position at Target Site step 306. If the treatment isacceptable 312, then operator would proceed. The next step in theprocedure can be to determine if more treatment sites are to be treated.If ‘No’ 313, the operator would then move on to Final Imaging 315 andthe remaining steps until END 322. If ‘Yes’ 314, the operator would thenre-position at the next target site 316 and repeat the steps forapplying a treatment. Once all treatments are complete, the operatorthen moves on to optional Final Imaging 315, where the operator canperform additional confirmatory imaging to ensure all targeting areaswere treated to his/her satisfaction. If ‘No’ 317, the operator wouldproceed back to ‘Re-position at next target site’ and perform additionaltreatments. If ‘Yes’ 318, the operator can then decide to perform one ormore acute biopsies and/or sputum samples 319 to compare to anypre-procedure biopsies and/or sputum samples 301 that can have beentaken. At a later date, follow-up imaging and/or, biopsies, and/orsputum samples 320 can be taken and compared to any other images or,biopsies, and/or sputum samples to help assess and/or document theoutcome of the therapy. The operator can then decide to delivermaterials, active agents, etc. 321 to assist in the normative healingprocess and as such further reduce the potential for peri-proceduralissues or complications. Moreover, this might further reduce the degreeor frequency of exacerbations, especially in the short term. Someexamples of these agents include isotonic saline gel, medicated films,antibacterials antivirals, antifungals, anti-inflammatories, etc. As aresult of exposing the tissue(s) to high-energy fields, the treatedtissue(s) can be conditioned for improved agent uptake. The procedurethen ends 322. The patient can then continue to be followed by aphysician and can undergo this entire procedure again, should thedisease or disorder recur and/or continue.

Thus, it is contemplated that in certain embodiments where the desiredclinical effect was not achieved or where it was achieved but thensubsequently the condition re-occurred, repeat procedures may bedesired. In these embodiments, it might be desired not only to re-treatcertain areas but also to target a different portion of the pulmonaryanatomy. Thus, the system 100 may be used to specifically re-treat thesame portion of tissue as the original treatment or a distinctlydifferent portion of tissue from the first intervention.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example, and notlimitation. Where methods described above indicate certain eventsoccurring in certain older, the ordering of certain events can bemodified. Additionally, certain of the events can be performedconcurrently in a parallel process when possible, as well as performedsequentially as described above.

II. Energy Delivery Algorithms

As mentioned previously, one or more energy delivery algorithms 152 areprogrammable, or can be pre-programmed, into the generator 104 fordelivery to the patient P. The one or more energy delivery algorithms152 specify electric signals which provide energy delivered to theairway walls W which are non-thermal, reducing or avoiding inflammation.In general, the algorithm 152 is tailored to affect tissue to itpre-determined depth and/or to target specific types of cellularresponses to the energy delivered. It may be appreciated that depthand/or targeting may be affected by parameters of the energy signalprescribed by the one or more energy delivery algorithms 152, the designof the catheter 102 (particularly the one or more energy delivery bodies108), and/or the choice of monopolar or bipolar energy delivery. In someinstances, bipolar energy delivery allows for the use of a lower voltageto achieve the treatment effect, as compared to monopolar energydelivery. In a bipolar configuration, the positive and negative polesare close enough together to provide a treatment effect both at theelectrode poles and in-between the electrode poles. This can spread thetreatment effect over a larger surface area thus requiring a lowervoltage to achieve the treatment effect, compare to monopolar. Likewise,this lower voltage may be used to reduce the depth of penetration, suchas to affect the epithelial cells rather than the submucosal cells. Inaddition, lower voltage requirements may obviate the use of cardiacsynchronization if the delivered voltage is low enough to avoidstimulation of the cardiac muscle cells.

It may be appreciated that a variety of energy delivery algorithms 152may be used. In some embodiments, the algorithm 152 prescribes a signalhaving a waveform comprising a series of energy packets wherein eachenergy packet comprises a series of high voltage pulses. In suchembodiments, the algorithm 152 specifies parameters of the signal suchas energy amplitude (e.g., voltage) and duration of applied energy,which is comprised of the number of packets, number of pulses within apacket, and the frequency of each pulse, to name a few. There may be afixed rest period between packets, or packets may be gated to thecardiac cycle and are thus variable with the patient's heart rate. Afeedback loop based on sensor information and an auto-shutoffspecification, and/or the like, may be included.

FIG. 13 illustrates an embodiment of a waveform 400 of a signalprescribed by an energy delivery algorithm 152. Here, two packets areshown, a first packet 402 and a second packet 404, wherein the packets402, 404 are separated by a rest period 406. In this embodiment, eachpacket 402, 404 is comprised of a first biphasic pulse (comprising afirst positive peak 408 and a first negative peak 410) and a secondbiphasic pulse (comprising a second positive peak 408′ and a secondnegative peak 410′). The first and second biphasic pulses are separatedby dead time 412 (i.e., a pause) between each pulse. In this embodiment,the biphasic pulses are symmetric so that the set voltage 416 is thesame for the positive and negative peaks. Here, the biphasic, symmetricwaves are also square waves such that the magnitude and time of thepositive voltage wave is approximately equal to the magnitude and timeof the negative voltage wave. The positive voltage wave causes cellulardepolarization in which the normally negatively charged cell brieflyturns positive. The negative voltage wave causes cellularhyperpolarization in which the cell potential is negative.

In some embodiments, each high voltage pulse or the set voltage 416 isbetween about 500 V to 10 kV, particularly about 500 V to 4000 V,including all values and subranges in between. In some embodiments, eachhigh voltage pulse is in range of approximately 1000 V to 2500 V whichtypically penetrates the airway wall W so as to treat or affectparticular cells somewhat shallowly, such as epithelial cells. In someembodiments, each high voltage pulse is in the range of approximately2600 V to 4000 V which typically penetrates the airway W so as to treator affect particular cells somewhat deeply positioned, such assubmucosal cells or smooth muscle cells. It may be appreciated that theset voltage 416 may vary depending on whether the energy is delivered ina monopolar or bipolar fashion. In some embodiments, the energy isdelivered in monopolar fashion and each high voltage pulse is in therange of approximately 2000 V to 3500 V, more particularly 2500 V. Inbipolar delivery, a lower voltage may be used due to the smaller, moredirected electric field. In some embodiments, the energy is delivered ina bipolar fashion and each pulse is in the range of approximately 100 Vto 1900 V, particularly 100 V to 999 V, more particularly approximately500 V to 800 V, such as 500 V, 550 V, 600 V, 650 V, 700 V, 750 V, 800 V.

It may be appreciated that in some embodiments the set voltage 416 isbetween about 50 V and about 4 kV or about 500 V and about 4 kV,including all values and subranges in between. And in other embodiments,the set voltage 416 is in a range of about 500 V to about 5 kV,including all values and subranges in between.

The number of pulses per unit of time is the frequency. In someembodiments, the has a frequency in the range 100 kHz-1 MHz. In someembodiments, the signal has a frequency in the range of approximately100-500 kHz which typically penetrates the airway W so as to treat oraffect particular cells somewhat deeply positioned, such as submucosalcells or smooth muscle cells. In some embodiments, the signal has afrequency in range of approximately 600 kHz-1 MHz which typicallypenetrates the airway wall W so as to treat or affect particular cellssomewhat shallowly, such as epithelial cells. It may be appreciated thatat frequencies at or 300 kHz, undesired muscle stimulation may occur.Therefore, in some embodiments, the signal has a frequency in the rangeof 500-800 kHz, such as 500 kHz, 550 kHz, 600 kHz, 650 kHz, 700 kHz, 750kHz, 800 kHz. In particular, in some embodiments, the signal has afrequency of 606 kHz. In addition, cardiac synchronization is typicallyutilized to reduce or avoid undesired cardiac muscle stimulation. Insome embodiments, biphasic pulses are utilized to reduce undesiredmuscle stimulation, particularly cardiac muscle stimulation. It may beappreciated that even higher frequencies may be used with componentswhich minimize signal artifacts.

In some embodiments, the time between packets, referred to as the restperiod 406, is set between about 0.1 seconds and about 5 seconds,including all values and subranges in between. In other embodiments, therest period 406 ranges from about 0.001 seconds to about 10 seconds,including all values and subranges in between. In some embodiments, therest period 406 is approximately 1 second. In particular, in someembodiments the signal is synced with the cardiac rhythm so that eachpacket is delivered between heartbeats, thus the rest periods coincideswith the heartbeats. In other embodiments wherein cardiacsynchronization is utilized, the rest period 406 may vary, as the restperiod between the packets can be influenced by cardiac synchronization,as will be described in later sections.

The cycle count 420 is the number of pulses within each packet.Referring to FIG. 13, the first packet 402 has a cycle count 420 of two(i.e. two biphasic pulses). In some embodiments, the cycle count 420 isset between 1 and 100 per packet, including all values and subranges inbetween. In some embodiments, the cycle count 420 is up to 5 pulses, upto 10 pulses, up to 25 pulses, up to 40 pulses, up to 60 pulses, up to80 pulses, up to 100 pulses, up to 1,000 pulses or up to 2,000 pulses,including all values and subranges in between.

The packet duration is determined by the cycle count. The higher thecycle count, the longer the packet duration and the larger the quantityof energy delivered. In some embodiments, packet durations are in therange of approximately 50 to 100 microseconds, such as 50 μs, 60 μs, 70μs, 80 μs, 90 μs of 100 μs.

The number of packets delivered during treatment, or packet count, mayinclude 1 packet, 2 packets, 3 packets, 4 packets, 5 packets, 10packets, 15 packets, 20 packets, up to 5 packets, up to 10 packets, upto 15 packets, up to 20 packets, up to 100 packets, or up to 1,000packets, including all values and subranges in between. In someembodiments, 5 packets are delivered, wherein each packet has a packetduration of 100 microseconds and set voltage of 2500 V. In someembodiments, 5 to 10 packets are delivered, wherein each packet has apacket duration of 100 microseconds and a set voltage of 2500 V, whichresults in a treatment effect that has increased uniformity. In someembodiments, less than 20 packets, wherein each packet has a packetduration of 100 microseconds and a set voltage of 2500 V, are deliveredto avoid affecting the cartilage layer CL. In some embodiments, a totalenergy-delivery duration between 0.5 to 100 milliseconds at a setvoltage of 2500 V can be optimal for the treatment effect.

In some embodiments, the dead time 412 is set between about 0 and about500 nanoseconds, including all values and subranges in between. In someembodiments, the dead time 412 is in a range of approximately 0 to 10microseconds, or about 0 to about 100 microseconds, or about 0 to about100 milliseconds, including all values and subranges in between. In someembodiments, the dead time 412 is in the range of 0.2 to 0.3microseconds.

It may be appreciated that the specific settings to desirably altertarget tissue are dependent on one another and the electrode design.Therefore, the embodiments provided herein depict specific waveformexample, and it is within the scope of this invention to use multiplewaveforms and/or characteristics in any combination to achieve thedesired tissue effects. A first example combination of parameters for anenergy signal comprises a frequency of 600 kHz, a voltage of 3000 V anda packet count of 10. A second example combination of parameters for anenergy signal comprises a frequency of 600 kHz, a voltage of 2500 V andpacket count of 5. A third example combination of parameters for anenergy signal comprises a frequency of 600 kHz, a voltage of 2300 V anda packet count of 20. The first example led to greater epithelial andsubmucosal gland treatment due to the higher voltage. The second exampleled to less epithelial and submucosal gland treatment due to the lowervoltage and lower packet count. The third example, yielded strongerepithelial treatment effect and a lower voltages do not penetrate deepenough to have the same treatment effect on submucosal glands thanhigher voltages.

FIG. 14 illustrates an example waveform 400 prescribed by another energydelivery algorithm 152. Here, two packets are shown, a first packet 402and a second packet 404, wherein the packets 402, 404 are separated by arest period 406. In this embodiment, each packet 402, 404 is comprisedof a first biphasic pulse (comprising a first positive peak 408 and afirst negative peak 410) and a second biphasic pulse (comprising asecond positive peak 408′ and second negative peak 410′). The first andsecond biphasic pulses are separated by dead time 412 between eachpulse. In this embodiment, the waveform 400 is asymmetric so that theset voltage is different for the positive and negative peaks. Thisasymmetrical waveform may result in a more consistent treatment effectas the dominant positive or negative amplitude leads to a longerduration of same charge cell membrane charge potential. In someembodiment, the first positive peak 408 has a set voltage 416 that islarger than the set voltage 416′ of the first negative peak 410. In someembodiments, asymmetry also includes pulses having pulse widths ofunequal duration. In some embodiments, the biphasic waveform isasymmetric such that the voltage in one direction (i.e., positive ornegative) is greater than the voltage in the other direction but thelength of the pulse is calculated such that the area under the curve ofthe depolarization equals the area under the curve of thehyperpolarization. Alternatively, the area under the curve of thedepolarization and hyperpolarization may be unequal.

FIG. 15 illustrates an example waveform 400 prescribed by another energydelivery algorithm 152. Again, two packets are shown, a first packet 402and a second packet 404, wherein the packets 402, 404 are separated by arest period 406. In this embodiment, each packet 402, 404 is comprisedof a first monophasic pulse 430 and a second monophasic pulse 432. Thefirst and second monophasic pulses 430, 432 are separated by dead time412 between each pulse. This monophasic waveform could lead to a moredesirable treatment effect as the same charge cell membrane potential ismaintain for longer durations. However, adjacent muscle groups will bemore stimulated by the monophasic waveform, compared to a biphasicwaveform.

FIG. 16 illustrates an example waveform 400 prescribed by another energydelivery algorithm 152. Again, two packets are shown, a first packet 402and a second packet 404, wherein the packets 402, 404 are separated by arest period 406. In this embodiment, each packet 402, 404 is comprisedthree biphasic pulses 440, 442, 444. And, rather than square waves,these pulses 440, 442, 444 are sinusoidal in shape. One benefit of asinusoidal shape is that it is symmetrical. Symmetry may assist inreducing undesired muscle stimulation.

Energy delivery may be actuated by a variety of mechanisms, such as withthe use of a button 163 on the catheter 102 or a foot switch 168operatively connected to the generator 104. Such actuation typicallyprovides a single energy dose. The energy dose is defined by the numberof packets delivered and the voltage of the packets. Each energy dosedelivered to the airway wall W maintains the temperature at or in thewall W below a threshold for thermal ablation, particularly thermalablation of the basement membrane BM. In addition, the doses may betitrated tor moderated over time so as to further reduce or eliminatethermal build up during the treatment procedure. Instead of inducingthermal effects, the energy does provides energy at a level whichinduces biological mechanisms and cellular effects ultimately leading tothe regeneration of healthy tissue.

III. Biological Mechanisms & Cellular Effects

As mentioned previously, the algorithm provides energy to the airwaywalls W at a level which induces biological mechanisms and cellulareffects while reducing or avoiding inflammation. Example biologicalmechanisms and cellular process are described herein, but are not solimited.

The energy provided to the airway walls W may cause a variety ofcellular effects which ultimately lead to the regeneration of healthylung airway tissue. Example cellular effects include removal ofparticular cell types, such as by detachment of the cells from theairway wall W (so that the detached cells can be carried away by naturalor induced methods) or by cell death (e.g. lysis and apoptosis). Othercellular effects include modification of particular cell types withoutremoval, such as reprogramming the cells or conditioning the cells forimproved agent uptake.

In some embodiments, particular cells are removed by detachment of thecells from the airway wall W. FIG. 17 illustrates an embodiment whereinenergy (indicated by arrows 200) is provided to the airway wall W by theone or more energy delivery bodies. In this embodiment, the energy 200has a targeted cell depth set to affect the epithelial layer E withoutextending beyond the basement membrane BM. The energy 200 is configuredto came particular epithelial cells, in this instance ciliatedpseudostratified columnar epithelial cells PCEC and goblet cells GC, todetach from the remaining epithelial layer (e.g. basal cells BC) and/orthe basement membrane BM. The detached cells are then free within thelung passageway, able to be removed by the natural process of expulsionor by interventional methods such as suction.

In other embodiments, particular cells are removed by cell death,wherein the affected cells die by lysis or apoptosis, ultimatelyremoving the cells from the airway wall W. FIG. 18 illustrates anembodiment wherein energy 202 is provided to the airway wall W by one ormore energy delivery bodies and again, the energy 202 has a targetedcell depth set to affect the epithelial layer E without extending beyondthe basement membrane BM. However, in this embodiment, the energy 202 isconfigured to cause particular epithelial cells, in this instanceciliated pseudostratified columnar epithelial cells PCEC and gobletcells GC, to die (as indicated by dashed line) while other cells (e.g.,basal cells BC) remain. Cell death can be achieved by a variety ofmechanisms. For example, in some embodiments, cell death occurs bydestruction of the cell membrane. In such embodiments, the deliveredenergy may destroy the lipid bi-layer of the cell membrane such that thecell membrane is unable to maintain the barrier function of the cell.Without a plasma membrane, the cell cannot maintain proper intracellularconcentrations of sodium, potassium, calcium and adenosine triphosphate(ATP). Consequently, the cell loses homeostasis and dies. In someembodiments, cell death occurs by disruption of intracellularorganelles. In such embodiments, the delivered energy may permanentlyimpede intracellular organelles from functioning. These organellesinclude endoplasmic reticulum, golgi apparatus, mitochondria, nucleus,nucleolus or others. Without the normal function of these intracellularorganelles, the cell dies. It may be appreciated that in some instances,both the cell membrane and intracellular organelles are targeted by thedelivered energy. Thus, if the delivered energy has only a partialeffect on the cell membrane or intracellular organelles, the cumulativeeffect on both targets will ultimately yield cell death.

After cell death, the inflammatory cascade ensues. Cell fragments andintracellular contents signal leukocytes and macrophages to enter theaffected area of the airway wall W. Over the course of hours to days,the dead cells are cleared from the area via phagocytosis. Unlikethermal ablation which damages the extracellular matrix, phagocytosis islimited to the cellular remains and not the collagen or matrixcomponents of the extracellular matrix.

In some embodiments, particular cells are not removed, rather thetargeted cells are modified or affected, such as reprogrammed. Forexample, in some embodiments, the ability of the goblet cells GC tosecrete stored mucus or produce mucus at all is altered. Or,modification causes the cilia C on ciliated pseudostratified columnarepithelial cells PCEC to regain their function and better expel mucus upthe airway. In other embodiments, ciliated pseudostratified columnarepithelial cells PCEC and goblet cells GC are unchanged but deeperstructures are primarily affected such as a reduction in smooth musclehypertrophy or neutralization of chronic inflammatory cells andcosinophils.

Whether the cells are removed or modified, the airway wall W regeneratesand restores normal function. It may be appreciated that in someinstances the epithelial cells may regenerate to their pre-treated stalebut the deeper cells, including the smooth muscle SM, eosinophils,submucosal glands SG, and chronic inflammatory cells, may be permanentlyreduced.

As mentioned previously, the algorithms may be tailored to affect tissueto a pre-determined depth and/or to target specific types of cellswithin the airway wall. For instance, various algorithms mayspecifically target the mucus layer M, the epithelial layer E, thebasement membrane BM, the lamina propria LP, the smooth muscle cells SM,the submucosa, submucosal glands SG, nerves N, or various combinationsof these. In one embodiment, the algorithm is configured to generateenergy that penetrates the epithelial layer E of the airway wall W up tothe basement membrane BM. Within this embodiment, a variety of differentcell types may be targeted. For example, the energy may be configured totarget the ciliated pseudostratified columnar epithelial cells PCEC andgoblet cells GC causing their removal while leaving the basal cells BCbehind. In such embodiments, the airway wall W may have abnormal andnon-functioning ciliated pseudostratified columnar epithelial cells PCECand hyperplastic, abnormal goblet cells GC causing mucus hypersecretion.The delivered energy causes the abnormal ciliated pseudostratifiedcolumnar epithelial cells PCEC and goblet cells GC to be removed, suchas by cell death or detachment, leaving the basal cells BC intact alongthe basement membrane BM. Recall, the ciliated pseudostratified columnarepithelial cells PCEC and goblet cells GC are connected to each other bytight junctions TJ and adherens junctions AJ. In addition, the ciliatedpseudostratified columnar epithelial cells PCEC and goblet cells GC areconnected to the basal cells BC by desmosomes D. In some embodiments,the energy is configured so as to overcome the tight junctions TJ andadherens junctions AJ, and additionally the desmosomes D, allowingremoval of ciliated pseudostratified columnar epithelial cells PCEC andgoblet cells GC. Likewise, the energy may be configured to allowpreservation of the hemidesmosomes H which connect the basal cells BC tothe basement membrane 126. Thus, the basal cells BC remain intact.

Removal of ciliated pseudostratified columnar epithelial cells PCEC andgoblet cells GC can reduce mucus production and mucus secretion by avariety of mechanisms. For example, such removal can mute the signalingmechanisms that lead to the expression of proteins found in mucin,thereby reducing mucus production. In particular, Muc5ac is a proteinfound in the mucin in the airway goblet cells GC that is encoded by theMUC5AC gene. There are several ligands and transcription factors thatare involved in Muc5ac expression. Interleukin-13 binds to a receptorthat includes the interleukin-4Rα subunit, activating Janus kinase 1(Jak1), leading to the phosphorylation of Stat6. There is no consensusStat6 binding site in the MUC5AC and Muc5ac promoter, but Stat6activation leads to increased expression of SPDEF (SAM pointeddomain-containing Ets transcription factor), which up-regulates multiplegenes involved in mucous metaplasia, and inhibits expression Foxa2,which negatively regulates Muc5ac. Several ligands bind ErbB receptors,including epidermal growth factor, transforming growth factor α,amphiregulin, and neuregulin, activating mitogen-activated proteinkinases (MAPK). Hypoxia-inducible factor 1 (HIF-1) also can be activateddownstream of ErbB receptors, and there is a conserved HIF-1 bindingsite in the proximal MUC5AC and Muc5ac promoter. Complement C3 andβ2-adrenergic-receptor signaling, also amplify Muc5ac production,whereas transcription factors such as Sox2, Notch, E2f4, and Mathprimarily regulate development.

In the case of removal of ciliated pseudostratified columnar epithelialcells PCEC and goblet cells GC, by cell death or detachment, thesignaling mechanisms that lead to Muc5ac expression are muted.Therefore, mucus is not produced, resulting in a decrease in mucus inthe airway. This leads to benefits in patients with COPD (chronicbronchitis, emphysema), asthma, interstitial pulmonary fibrosis, cysticfibrosis, bronchiectasis, acute bronchitis and other pulmonary diseasesor disorders.

Removal of such epithelial cells can also reduce mucus secretion by avariety of mechanisms. In particular, removal of the mucus producinggoblet cells GC leaves no cells to secrete mucus into the airway.Secretion of mucus is induced by the molecular mechanism of mucinexocytosis. A mucin-containing secretory granule is docked to the plasmamembrane by the interaction of a granule-bound Rab protein with aneffector protein that acts as a tether to Munc18, which binds the closedconformation of Syntaxin anchored to the plasma membrane. Secretion istriggered when ATP binds to P2Y2 purinergic receptors (P2Y2R) coupled toGq, activating phospholipase C (PLC, which generates the secondmessengers diacylglycerol (DAG) and inositol triphosphate (IP3). DAGactivates Munc1314 to open Syntaxin so it can form a four-helix SNARE(soluble N-ethylmaleimide-sensitive factor attachment protein receptor)complex with SNAP-23 (synaptosomal-associated protein 23) and VAMP(vesicle-associated membrane protein), drawing together the granule andplasma membranes. IP3 induces the release of calcium from IP3 receptors(IP3R) in the endoplasmic reticulum (ER), activating Synaptotagmin toinduce final coiling of the SNARE complex, which results in fusion ofthe membranes and release of the mucins.

With the removal of these epithelial cells, the signaling mechanismsthat lead to mucin exocytosis are muted. Therefore, less mucus issecreted, resulting in a decrease in mucus in the airway. This leads tobenefits in patients with COPD (chronic bronchitis, emphysema), asthma,interstitial pulmonary fibrosis, cystic fibrosis, bronchiectasis, acutebronchitis and other pulmonary diseases or disorders.

In some embodiments, the basal cells BC left on the basement membrane BMare able to regenerate normal goblet cells GC and normal ciliatedpseudostratified columnar epithelial cells PCEC, thereby inducingreverse remodeling of the disease to reduce the mucus hypersecretion. Insome embodiments, ciliated pseudostratified columnar epithelial cellsPCEC additionally repopulate by migration from surrounding areas of theairway wall W to assist in regeneration of healthy tissue in the targetarea. The goblet cells GC typically regenerate at a lower level ascompared to mild, moderate, or severe goblet cell hyperplasia that ispresent before the application of energy. The newly regenerated gobletcells GC are significantly less productive of mucus and the newlyregenerated ciliated pseudostratified columnar epithelial cells PCECregrow normally functioning cilia C, which more easily expel mucus M.Thus, healthy new target tissue can be regenerated within days of theprocedure. This dramatically reduces symptoms of cough and mucushypersecretion in patients which results in fewer and less severeexacerbations and improvement in qualify of life.

It may be appreciated that in other embodiments, the energy may beconfigured to target the abnormal goblet cells CG causing their removal,such as by cell death or detachment, leaving behind the ciliatedpseudostratified columnar epithelial cells PCEC and the basal cells BC.Removal of the abnormal goblet cells CG can reduce mucus productionand/or mucus secretion by many of the mechanisms described above.Likewise, the energy may be configured to target the abnormal ciliatedpseudostratified columnar epithelial cells PCEC causing their removal,such as by cell death or detachment, leaving behind the goblet cells CGand the basal cells BC. Likewise, the energy may be configured to targetthe abnormal basal cells BC causing their removal, such as by cell deathor detachment, leaving behind the ciliated pseudostratified columnarepithelial cells PCEC and goblet cells GC. In any of these combinationsof cell removal, it may be appreciated that the remaining cells may beadditionally modified or affected by the delivered energy or by energydelivered subsequently. For example, abnormal goblet cells CG leftbehind may be modified so as to reduce mucus production and/or mucussecretion while remaining intact. It may also be appreciated that cellpopulations may be partially removed wherein some cells of a particularcell type are removed by the delivered energy while some remain,optionally modified.

In other embodiments, the algorithm is configured to generate energythat penetrates the epithelial layer E of the airway wall W up to andincluding the basement membrane BM. In such embodiments, changes to theepithelial layer E may occur as described above. Additionally, thebasement membrane BM may be affected by the delivered energy so as toassist in remodeling the airway wall W to a healthy state. In someembodiments, the basement membrane BM is altered so as to stabilize orreduce the thickness of the basement membrane BM. Basement membrane BMthickening is a feature of many pulmonary diseases, including chronicbronchitis and asthma. Thus, the delivered energy may target thebasement membrane BM so as halt or reverse such thickening. In someembodiments, such altering of the basement membrane BM affects theability of cells, such as neutrophils, and inflammatory molecules, suchas cytokines, to cross the basement membrane BM, thus assisting inregeneration of a healthy airway wall W.

In some embodiments, the algorithms configured to generate energy thatpenetrates the epithelial layer E of the airway wall W and beyond thebasement membrane BM. The position of various layers of the airway wallW beyond the basement membrane BM may vary due to variations in theanatomy along the lung passageways. For example, the position of thesmooth muscle layer SM may vary along the length of the lung passageway,ranging from adjacent to the basement membrane BM to below the laminapropria LP. Thus, energy delivery may be titrated to target selectlayers of the airway wall W for a particular lung passageway segment.For example, the algorithm may be chosen or adjusted to affect thesmooth muscle layer SM at its particular location. Smooth musclehypertrophy is a feature of many pulmonary diseases, including chromebronchitis, asthma and several other airway diseases resulting in airwayhyperactivity. In some embodiments, the delivered energy induces celldeath of smooth muscle cells. This may reduce airway hyperactivity andcause desired bronchodilation.

In some embodiments, the algorithm is chosen or adjusted to affect thesubmucosal glands SG. Submucosal glands overproduce and hypersecretemucus in diseased airways. In some embodiments, the delivered energyinduces cell death of submucosal glands SG. A reduction in submucosalglands SG may lead to less mucus in the airways and improvement inpatient outcomes.

In some embodiments, the algorithm is chosen or adjusted so that thedelivered energy affects the lamina propria LP. The lamina propria LP iscomprised of loose connective tissue. The connective tissue and matrixarchitecture of the lamina propria LP is vary compressible and elasticwhich allows expansion of the lung passageways. In addition, the loosestructure allows for the presence of many cell types. The cellpopulation of the lamina propria LP is variable and can include, forexample, fibroblasts, lymphocytes, plasma cells, macrophages,eosinophilic leukocytes, and mas cells. Patients with airway diseaseoften have chronic inflammation, specifically increased populations oflymphocytes and macrophages. In some embodiments, the delivered energyreduces the quantity of inflammatory cells, particularly lymphocytes,macrophages and/or eosinophils, thus reducing inflammation. Such energyremoves, such as by cell death, cells from the lamina propria LP whilemaintaining the extracellular matrix. By maintaining the matrixarchitecture, stem cells and/or other cells are able to repopulate thematrix forming a healthy tissue. This is in contrast to fibrosis orother scar forming mechanisms wherein the layers of the airway wall W,including the extracellular matrix, are permanently changed, such as bymelting or collapsing the layers together. In addition, the cartilagelayer CL is not injured so as to maintain the structural integrity ofthe airway and prevent collapse.

Thus, it may be appreciated that one or more algorithms may be used toprovide energy to affect one or more layers of the airway wall W. Theenergy may penetrate to a particular depth within the airway wall W,affecting numerous layers extending from the surface of the wall W tothe particular depth. Or, the energy may be configured to affect cellsat a particular depth without affecting surrounding layers. The affectsmay include cell removal, such as by cell death or detachment, ormodification of the cell, such as to change particular functioning ofthe cell. In some instances, only a portion of cells of the same type orin the same layer may be affected by the delivered energy. Optionally,additional energy, either utilizing the same or different algorithm, maybe delivered to affect a larger portion or all of the cells of the sametype or in the same layer. Or, additional energy, either utilizing thesame or different algorithm may be delivered to increase the affect. Forexample, additional energy may result in cell removal of previouslymodified cells. Still further, additional energy, either utilizing thesame or different algorithm, may hebe delivered to affect a differentportion or depth of the airway wall.

The actual mechanisms by which the cells are removed or modified mayvary depending on the algorithm 152 energy delivery bodies 108, andpatient anatomy, to name a few. In some embodiments, cells are removed(e.g. detached) by dielectrophoresis.

Dielectrophoresis describes the movement of particles under theinfluence of applied electric fields which are non-uniform. Thedielectrophoretic motion is determined by the magnitude and polarity ofthe charges induced in a particle by the applied field. The dipolemoment induced in a particle can be represented by the generation ofequal and opposite charges at the particle boundary. Since this inducedcharge is not uniformly distributed over the particle surface, itcreates a macroscopic dipole. Since the applied field is non-uniform,the local electric field and resulting force on each side of theparticle will be different. Thus, depending on the relativepolarizability of the particle with respect to the surrounding medium,it will be induced to move either towards the inner electrode and thehigh-electric-field region (positive dielectrophoresis) or towards theouter electrode, where the field is weaker (negative dielectrophoresis).The dielectrophoretic force is a function of cell volume andpolarization, the conductivity and permittivity of the surroundingmedia, and the frequency and spatial gradients of the magnitude of thegenerated electric field.

In some embodiments, removal of the abnormal epithelial cells, is suchas ciliated pseudostratified columnar epithelial cells PCEC and gobletcells GC, is the result of dielectrophoresis induced by one or moreenergy pulses delivered by the energy delivery body 108. In particular,in some embodiments, the epithelial layer E is separated by the actionof dielectrophoresis, wherein the abnormal ciliated pseudostratifiedcolumnar epithelial cells PCEC and goblet cells GC are pulled away fromthe anchored basal cells BC and removed from the airway wall W. Recall,the basal cells BC are connected to the basement membrane BM byhemidesmosomes H whereas the basal cells BC connect to the goblet cellsGC and ciliated epithelial cells EC via desmosomes D. The energyparameters and electrode configuration can be designed such that thedesmosomes connections D separate but the hemidesmosomes H remain intactthereby removing the surface cells, leaving the basal cells BCsubstantially intact, and ready to regenerate epithelium.

FIG. 19 schematically illustrates removal of epithelial cells by adielectrophoresis effect. Here, a distal portion of an embodiment of acatheter 102 having an energy delivery body 108 is illustratedpositioned within a lung passageway. Energy 204 is delivered from theenergy delivery body 108, as indicated by dashed electric field lines.The electric field is non-uniform due to the shape of the energydelivery body 108 and the placement of the return electrode 140 which isapplied externally to the skin of the patient P. In this embodiment, theenergy delivery body 108 is positively charged. This is thestrongest/most concentrated pole of the electric field. The returnelectrode 140 is negatively charged and is the weakest pole of theelectric field. Consequently, the non-uniform electric field causesdetachment and displacement of the epithelial cells (e.g., ciliatedpseudostratified columnar epithelial cells PCEC and goblet cells GC)from the airway walls W (as indicated by downward arrows). Theepithelial cells are then removed by natural or induced mechanisms.

It may be appreciated that in some embodiments, the cells are removed ormodified by other mechanisms, such as electroporation. Reversibleelectroporation in a non-thermal technique in which short, high voltagepulses generate intense electric fields that increase cell membranevoltage, leading to the creation of pores in cell membranes (e.g.,plasma membrane). These pores allow chemicals DNA, and/or other agentsto be introduced into the cell. Thus, in some embodiments, reversibleelectroporation may be used, such as to modify cells in the airway wallW, such as to increase uptake of drugs or agents. Irreversibleelectroporation (IRE) is a non-thermal ablation technique in whichshort, high voltage pulses generate intense electric fields thatincrease cell membrane voltage, leading to the creation of pores in cellmembranes (e.g., plasma membrane), inducing necrosis of cells, withoutsubstantial protein denaturation. Thus, in some embodiments,irreversible electroporation may be used, such to remove cells by celldeath. It may also be appreciated that in some embodiments, cells areremoved or modified by combination of mechanism, such as a combinationof dielectrophoresis and electroporation.

Alternatively or in addition to affecting tissue cells within the airwaywall W, the delivered energy may affect pathogens resident in or nearthe airway wall W. Example pathogen types include without limitationbacteria (e.g., Haemophilus influenzae, Streptococcus pneumoniae,Moraxella catarrhalis, Staphylococcus aureus, Pseudomonas aeruginosa,Burkholderia cepacia, opportunistic gram-negatives, Mycoplasmapneumoniae, and Chlamydia pneumoniae), viruses (rhinoviruses,influenze/parainfluenza viruses, respiratory syncytial virus,coronaviruses, herpes simplex virus, adenoviruses), and other organisms(e.g., fungi).

In some embodiments, the pulmonary tissue modification system 100 mayadditionally or alternatively be useful for impacting pathogens foundwithin a lumen of an airway (e.g. within the mucus layer M) or withintissue layers of the airway wall W of a patient such that infection iscontrolled, reduced, and/or eliminated. In some embodiments, the energyoutput from system 100 affects the mucus layer M and any pathogens thatmay be resident in or near the airway. The mucus layer M may become lessviscous, thus making if easier for the patient to expel via coughing.The pathogens may be killed or programmed to die (e.g., apoptosis),thereby reducing or eliminating infection.

In some embodiments, the system 100 may assist the patient in developingantibodies or other commensal and supportive immune responses totargeted pathogens, improving future immunity and resistance to thatpathogen in the future. Since the system 100 affects pathogens in asubstantially non-thermal manner, leading to cell death, the cellularfragments still contain proteins. As these more intact proteins arereleased into the local environment and the circulation, the immunesystem develops new methods of surveillance, recognition and threatresponses to these challenges, which can enhance host defense from thosechallenges or pathogens in the future.

As mentioned previously, it may be appreciated that the energy signalparameters may be manipulated to cause differing effects, such asdiffering depths of penetration. In some instances, the system 100 canbe configured such that only the mucus layer M and any residentpathogens are affected. In some instances, the separation of theepithelial layer E occurs. In some instances, the system 100 can beconfigured such that the epithelial layer E separation occurs, pathogensare affected, and/or deeper structures are affected via a single energydelivery algorithm. In some instances, the generator can have a varietyof energy delivery algorithms stored within it, and the user can applytwo or more of these algorithms to tailor therapy to an individualpatient. This may be done in a single therapy session or multipletherapy sessions in order to address the needs of individual patients.

In some instances, IT can be desirable to affect deeper cells includingsmooth muscle cells SM submucosal glands SG, and/or nerves N. Apatient's pathology can be more complex than mucus hypersecretion causedby the epithelium E and therefore the procedural intent is to affectdeeper structures Airway smooth muscle cells SM are known to contributeto bronchial hyper-responsiveness, submucosal glands SG can contributeto severe mucus hypersecretion, and nerves N innervate both submucosalglands SG and airway smooth muscle SM. Alternatively, patients withmixed pathologies such as asthma and chronic obstructive pulmonarydisease (COPD) (e.g., Asthma-COPD Overlap Syndrome) can benefit from aprocedure that targets several mechanisms (e.g., mucus hypersecretion,smooth muscle hypertrophy, cilia dysfunction, and/or the like) and/ortarget tissues. The energy dose can be titrated (e.g., iterativelymodified based on sensor and/or other feedback) to affect structuresdeep to the epithelium E. In some instances, as the energy dose isincreased, the submucosal glands SG undergo a mild partial membranelysis or a significant loss of structural integrity. Uniquely and unlikethermal energy, the lamina propria LP, which is a cell layer that sitsbetween the epithelium E and submucosal glands SG, remains unchanged. Athermal energy source would cause significant changes in the structureof the extracellular matrix and cause fibrosis.

In addition to the submucosal glands SG, the smooth muscle SM can beaffected depending on the dosing, ranging from focal changes toobliteration which causes removal of the epithelium E over days toweeks. The cartilage layer CL, the deepest structure in the airway wall,is unaffected by the energy and shows no signs of inflammation ornecrosis, acting as an insulative barrier.

IV. Sensors

In some embodiments, one or more sensors 160 are included in the system100 to measure one or more system or tissue parameters. Example sensors160 include temperature sensors, impedance sensors, resistance sensor,surface conductance sensors, membrane potential sensors, capacitancesensors, and/or force/pressure sensors, or combinations thereof. Thus,parameter measured by sensors 160 can include impedance, membranepotential or capacitance, and/or temperature, to name a few. Sensors 160can be used for (a) obtaining a baseline measure, (b) measuring aparameter during the delivery of energy, and/or (c) measuring parameterfollowing energy delivery, among others.

Sensors 160 can be positioned on energy delivery bodies 108, adjacent toenergy delivery bodies 108, or in any suitable location along the distalportion of the catheter 102. Temperature sensors can monitor thetemperature of an electrode and/or the electrode/tissue interface.Impedance sensors can monitor the impedance of the tissue across any twoelectrodes. Conductance sensors can monitor the transmission ofelectrical energy across any two electrodes. Force/pressure sensors canmonitor the amount of force or pressure that the electrodes are placingon the tissue.

This sensor information can be used as feedback to the system in orderto, as non-limiting examples, determine proper deployment of energydelivery bodies 108, drive a therapeutic algorithm 152, and/or stopenergy delivery for safety reasons. Sensors 160 can also be used tosense when an adequate treatment is achieved. An algorithm 152 withinthe generator 104 can also use the sensed data to automatically titratethe therapeutic algorithm 152 such that the target tissue treatment isachieved. Said another way, one or more parameters and/or aspects of thetherapeutic algorithm can be modified based on the sensor data in aniterative manner. For example, in some embodiments, the power and/orenergy duration can be increased or decreased based on the sensor data.

A. Impedance Sensors

1. Ensuring Proper Placement of Energy Delivery Bodies

In some embodiments, one or more impedance sensors are used to determineif the energy delivery bodies 108 are properly inserted and deployed inthe airway of the lung. In some embodiments, a short duration, lowvoltage signal is delivered to the energy delivery bodies 108 duringtheir placement and deployment/expansion within the targeted area of theairway. Based on measured electrical current feedback received by thegenerator 104 from the one or more impedance sensors, the generator'sprocessor 154 performs a calculation using the set voltage and actualcurrent to calculate the impedance. Calculated impedance is thencompared to impedance values that are considered acceptable for theproperly inserted and deployed energy delivery bodies 108. If thecalculated impedance is outside of the range of acceptable impedances,the generator 104 displays a specific message and/or emits a specificsound alerting the operator. For example, if the energy delivery bodies108 are still within the bronchoscope 112, the generator 104 may measurea very high impedance outside of the acceptable range. In suchinstances, the generator may then display a message (e.g., CheckElectrode Position) until the operator repositions the energy deliverybodies 108 into the airway where the impedance is significantly lowerand within the acceptable range. At this point, the message may change(e.g., Ready).

It may be appreciated that other types of sensors, such as temperature,force or pressure sensors may additionally or alternatively be used toverify electrode to tissue contact prior to initiation of treatment. Itmay also be appreciated that sufficient contact between electrodes andthe walls of the airway is an important factor for effective treatment.Solid and consistent contact is desired satisfactorily couple the energyfrom the electrode to the tissue and to achieve desired tissue effects.

2. Ensuring Proper Functioning of Catheter

In some embodiments, one or more impedance sensors are utilized todetermine if the catheter 102 is functional or potentially defective. Insuch embodiments, a short duration, low voltage signal (e.g., a signalhaving a duration from 1-5 packets, and a voltage of about 500 V) isdelivered to the energy delivery bodies during their placement anddeployment/expansion within the targeted area. Based on the measuredelectrical current feedback received by the generator 104, thegenerator's processor 154 performs a calculation using the set voltageand actual current to calculate the impedance. Calculated impedance iscompared to the impedance values that are considered acceptable for acatheter that is functioning properly. If the calculated impedance isoutside of the range of acceptable impedances, the generator 104optionally displays a specific message and/or emits a specific soundalerting the operator. For example, if the catheter is defective, theimpedance may be very high. In this embodiment, the generator 14displays a message (e.g., ‘Replace Catheter’). Once replaced, thegenerator 104 may then defect a much lower impedance within theacceptable range and display another message (e.g., ‘PositionCatheter’). Thus, impedance measurements can be used to avert a safetyconcern by detecting a malfunctioning catheter.

3. Modifying the Energy Algorithm

In some embodiments, impedance measurements can be made prior to orafter applying energy in order to define which energy delivery algorithm152 to apply and/or the need to apply additional energy to the targetlocation. In some embodiments, pre-treatment impedance measurements canbe used to determine the settings of various signal parameters. In otherembodiments, sensors can be used to determine if the energy-deliveryalgorithm should be adjusted.

In some embodiments, the impedance measurement is performed as follows.A short duration, low voltage signal is delivered to the energy deliverybody 108 via a generator (e.g., the generator 104) once positioned as atargeted area within a lung passageway. Based on the measured electricalcurrent feedback received by the generator 104, the generator 104performs a calculation using the set voltage and actual current tocalculate the impedance. The calculated impedance is compared toimpedance values that are considered acceptable for the measuredimpedance. Then, the energy deliver algorithm 152 is modified ortailored based upon the measured impedance. Parameters that can beadjusted include, but are not limited to, voltage, frequency, restperiod, cycle count, dead time, packet count or number of packets, or acontinuation thereof. Thus, a feedback control loop can be configured tomodify a parameter of energy delivery based on the measured one or moresystem or tissue parameters.

In some embodiments, one or more impedance sensors are used to monitorthe electrical properties of the tissue. Impedance values can beregarded as an indicator of tissue state. In some embodiments, impedanceis measured at different frequencies to provide an impedance spectrum.This spectrum characterizes the frequency dependent, or reactive,component of impedance. Tissue has both resistive and reactivecomponents; these are components of complex impedance. Reactance is thefrequency dependent component of impedance that includes tissuecapacitance and inductance. Changes in the state of the tissue canresult in changes to overall impedance as well as to changes in theresistive or reactive components of complex impedance. Measurement ofcomplex impedance involves the conduction of a low voltage sensingsignal between two electrodes. The signal can include but not be limitedto a sine wave. Changes in complex impedance, including changes inresistance or reactance, can reflect the state of treated tissue andtherefore be used as indicators that treatment is affecting tissue, notaffecting tissue, and/or that treatment can be complete. Impedancevalues can also change depending on the contact conditions between thesensors and airway tissue. In this way, sensors can also be used todetermine the state of contact between electrodes and the tissue.

In some instances, the generator 104 instructs the user that additionalenergy delivery at the target location is not seeded. Optionally, thegenerator 104 displays a specific message and/or emits a specific soundalerting the operator as to which energy delivery algorithm 154 has beenselected, or that treatment is complete at that target location. Thus,the generator 104 can be configured to automatically select theappropriate algorithm for a particular measured impedance or shut offthe delivery of energy signals if the treatment is determined to becompleted. Further, impedance or other sensors can be used to determinethat a treatment should be automatically stopped due to a safetyconcern.

B. Temperature Sensors

In some embodiments, one or more temperature sensors are used to measureelectrode and/or tissue temperature during treatment to ensure thatenergy deposited in the tissue does not result in clinically significanttissue heating. In some embodiments, the temperature measured at or nearthe electrodes is also used to determine the state of contact betweenthe electrode and tissue prior to treatment. This can be achieved byapplying energy at a level sufficient to generate heat but insufficientto cause substantial thermal injury. The temperature may differ in itssteady state value or in its variability depending upon whether theelectrode is pressed against the airway wall, moving, or suspended inthe airway lumen.

In some embodiments, one or more temperature sensors are disposed alongthe surface of one or more energy delivery bodies 108 so as to contactthe tissue and ensure that the tissue is not being heated above apre-defined safety threshold. Thus, the one or more temperature sensorscan be used to monitor the temperature of the tissue during treatment.In one embodiment, temperature changes that meet pre-specifiedcriterion, such as temperature increases above a threshold (e.g., 40°C., 45° C., 50° C., 60° C., 65° C.) value, can result in changes toenergy delivery parameters (e.g., modifying the algorithm) in an effortto lower the measured temperature or reduce the temperature to below thepre-set threshold. Adjustments can include but not be limited toincreasing the rest period or dead time, or decreasing the packet count.Such adjustments occur in a pre-defined step-wise approach, as apercentage of the parameter, or by other methods.

In other embodiments, one or more temperature sensors monitor thetemperature of the tissue and/or electrode, and if a pre-definedthreshold temperature is exceeded (e.g., 65° C.), the generator 104alters the algorithm to automatically cease energy deliver. For example,if the safety threshold is set at 65° C. and the generator 104 receivesthe feedback from the one or more temperature sensors that thetemperature safety threshold is being exceeded, the treatment can bestopped automatically.

C. Sensors to Monitor Electrode Contact

In some embodiments, multiple sensors (e.g., temperature, impedance,force, pressure etc.) are placed in various locations, such ascircumferentially, on the surface of the one or more energy deliverybodies 108. In such configurations, the sensors may be used to indicateif the contact between the surface of the one or more energy deliverybodies 108 and the bronchial airway wall surface is sufficient, such assuitably circumferential and/or stable. If sensors indicate that thecontact is not sufficient, such as not circumferential (e.g.,non-uniform temperature, impedance, force etc.) and/or stable (e.g.,continuously changing temperature, impedance, force, etc.), the operatormay adjust the level of the expansion for the one or more energydelivery bodies or choose a catheter 102 with different sized energydelivery bodies 108 that better match the internal diameter of thebronchus/bronchi that are being treated. In some embodiments, thegenerator 104 is configured to interpret the degree, quality, and/orstability of contact and provide the operator feedback to aid in theproper positioning of energy delivery bodies. For example, as theoperator is in the process of positioning the one or more energydelivery bodies which is not in circumferential contact, the userinterface 150 on the generator 104 may display a message such as “PoorContact”.

In some embodiments, force or pressure sensors can be used to detect andmeasure the contact force between the energy delivery bodies and thewalls of the airway and thereby determine the contact conditions betweenenergy delivery bodies and tissue.

It may be appreciated that any of the system 100 embodiments disclosedherein can incorporate one or more sensors to monitor the application ofthe therapy.

V. Cardiac Synchronization

In some embodiments, the energy signal is synchronized with thepatient's cardiac cycle to prevent induction of cardiac arrhythmias.Thus, the patient's cardiac cycle is typically monitored with the use ofan electrocardiogram (ECG). Referring to FIG. 20, a typical ECG tract600 includes a repeating cycle of a P wave 602 representing atrialdepolarization, a QRS complex 604 representing ventriculardepolarization and atrial repolarization, and a T wave 606 representingventricular repolarization. To safely deliver energy within the airwayin close proximity to the heart, synchronization between energy deliveryand the patient's cardiac cycle is employed to reduce the risk ofcardiac arrhythmia. High voltage energy can trigger a premature actionpotential within the cardiac muscle as the delivered energy increasesthe cardiac muscle cell membrane permeability allowing ion transport,which can induce cardiac arrhythmias, especially ventricularfibrillation. To avoid cardiac arrhythmias, the electrical energy isdelivered to the airway in a fashion that is outside the “vulnerableperiod” of the cardiac muscle. Within one cardiac cycle (heartbeat), thevulnerable period of the ventricular muscle is denoted on an ECG by theentire T wave 606. Typically, for ventricular myocardium, the vulnerableperiod coincides with the middle and terminal phases of the T wave 606.However, when high energy pulses are delivered in close proximity to theventricle, the vulnerable period can occur several milliseconds earlierin the heartbeat. Therefore, the entire T wave can be considered to bewithin the vulnerable period of the ventricles.

The remaining parts of a cardiac cycle are the P wave 602 and the QRScomplex 604, which both include periods when atrial or ventricularmuscle is refractory to high voltage energy stimuli. If high voltageenergy pulses are delivered during the muscle's refractory period,arrhythmogenic potential can be minimized. The ST segment 608 (intervalbetween ventricular depolarization and repolarization) of the firstcardiac cycle and the TQ interval 610 (interval including the end of thefirst cardiac cycle and the mid-point of the second cardiac cycle) arethe periods where high voltage energy can be delivered without inductionof cardiac arrhythmia due to the cardiac muscle depolarized state(refractory period). FIG. 20 includes shaded boxes that indicate exampleportions of the cardiac cycle during which energy can be applied safely.

FIG. 21 is a flowchart depicting an embodiment of a method forsynchronizing the delivery of energy with the cardiac cycle, accordingto some embodiments. In this embodiment, the electrocardiogram (ECG) isacquired by an external cardiac monitor 170 (such as the cardiacmonitors available from AccuSync Medical Research Corporation)operatively connected to a communications port 167 on the energyproducing generator 104, although it is understood that any suitablemonitor may be employed. Here, the cardiac monitor 170 is used tocontinuously acquire the ECG, analyze one or more cardiac cycles, andidentify the beginning of a time period where it is safe to applyenergy. In some embodiments, when the cardiac monitor 170 detects thisevent/beginning (e.g., the R wave of an ECG trace), it sends a lowvoltage transistor to transistor logic (TTL) pulse (e.g., ≤5 V) to thecommunications port 167. At the start step 650, the processor 154 of theenergy producing generator 104 monitors (at step 652) the communicationspost 167 to determine if the cardiac sync pulse is detected. If a TTLpulse is not detected (at step 654) by the generator 104, the userinterface 150 is used to inform the user (at step 656). For example, theuser interface 150 may display a solid red heart and/or any othersuitable visual indicator. Once a cardiac sync pulse is detected (atstep 658) by the generator 104, the user interface 150 is used to informthe user (at step 660). For example, the solid red heart may turn to ayellow blinking heart, turning on at the time the cardiac sync pulse isdetected.

Because the external cardiac monitor 170 can send false TTL pulses andbecause the generator should not allow treatment to continue if thepatient's heart rate is outside of the normal expected limits, iserratic, and/or has a widened QRS complex not associated with/differentfrom the patient's baseline rhythm, the next step can involve checkingthe heart rate to establish confidence in the TTL pulse (i.e., cardiacsync pulse) (at step 662). In one embodiment, the processor 154 of thegenerator 104 is used to monitor the TTL pulses and calculate the timebetween each beat, referred to as Δt1, Δt2, Δt3, Δt4, Δt5. These valuescan be stored within the data storage module 156 of the generator 104 asa rolling buffer having the last five Δt calculations. Next, the averageof those five values can be calculated, referred to as Δt-ave. The nextone or more TTL pulses detected can be used to calculate the next Δt(s)(e.g., Δt6, Δt7, etc.), which can also be stored in the data storagemodule 156. For example, two TTL pulses can be utilized.

Next, the algorithms module 152 of the generator 104 is used to comparethese values to a set of criteria that, if met, provide confidence thatthe patient's heart rhythm is normal/consistent and that the TTL pulseis reliable. For example, the heart rate can be calculated and checkedto ensure it is between 40-150 beats per minute (bpm). In this example,Δt6 and Δt7 can also be compared to Δt-ave to verify that the heart rateis not erratic. In one embodiment, Δt6 and/or Δt7 can be within ±15% ofΔt-ave in order to continue. In this example, both criteria must be metin order to confirm confidence (at step 664); however, in otherembodiments, both criteria may not be required. Once confidence isconfirmed, the user interface 150 can be used to inform the user that itis safe to continue (at step 666). For example, the yellow flashingheart on the user interface 150 can change to a green flashing heart.Next, the user 150 is used to direct the user to charge the high energystorage unit (e.g., one or more capacitors) of the generator 104. In oneexample, the user interface 150 displays a soft-key labeled ‘Charge’,which the user may press to charge the high energy storage unit. If thecharge button has not been pressed (at step 668), the processor 154continues to check heart rate and confidence in the TTL signals.

Once the processor 154 recognizes that the charge button has beenpressed (at step 670), the processor 151 continues to check heart rateand confidence in the TTL signals (at step 672). During that time, if apredefined/predetermined amount of time has passed (e.g., about 30, 40,50, 60, or up to 120 seconds, including all values and sub ranges inbetween) without verification that the heart rate and TTL confidence isestablished (at step 674, the system aborts the charging mode andreverts to the system status wherein it is checking heart rate andestablishing confidence in the cardiac sync pulse (at step 662). If thetimeout is not reached (step 676), the user interface 150 informs theuser (at step 678) until confidence is established (at step 680). Theuser interface 150 can change such that the soft-key is how labeled‘Ready’. The system 100 is now waiting for the footswitch 168 to bepressed.

While the system 100 waits for the footswitch 168 to be pressed (at step348), it continues to monitor heart rate and check for confidence (672).Another timeout can be predefined (e.g., about 30, 40, 50, 60, or up to120 seconds, including all values and sub ranges in between), such thatif the user does not press the footswitch 168 within that time (e.g.,timeout is reached, as illustrated, at step 674), the system abortsbeing ready so deliver energy and returns to the system status whereinit is checking heart rate and establishing confidence in the TTL pulses(at step 662). Once the user presses the footswitch (at step 684),energy delivery can commence (at step 686). However, the generator 104can be configured to wait until the next cardiac pulse is detected tofurther ensure that energy delivery occurs after the R-wave is detected.In one embodiment, the energy is not delivered until about 50milliseconds after the leading edge of the TTL pulse is detected,however this value could range from about 0-300 milliseconds. The firstenergy packet can then be delivered (at step 686). The processor 104then checks to determine if all packets have been delivered (at step688). If not, the processor 154 continues to monitor heart rate andcheck confidence in the TTL pulses (at step 690) and energy delivery cancontinue once confidence in the cardiac sync pulse (at step 662) isre-established.

In some instances, it may be beneficial to ignore TTL pulses immediatelyfollowing energy delivery, as they may be false triggers caused by thehigh voltage energy being delivered. For example, the processor 154 canignore TTL pulses for about 400 ms after energy is delivered or about450 ms after the leading edge of the last TTL pulse. In othersituations, the TTL pulses can be ignored for about 50 ms- to about 1second, including all values and sub ranges in between. Once theprocessor detects the next TTL pulse, the next Δt can be calculated andcompared against the criteria (at step 690) previously defined (i.e.,based on a rolling average). Due to the potential for transient delaysin the heart beat following energy delivery, if the next Δt fallsoutside of the criteria, it is simply ignored. Then, the next Δt canthen be calculated and compared against the criteria previously defined.If the criteria are met (at step 700), the next packet is delivered (atstep 686). If all packets have not been delivered, the system continuesto monitor the heart rate and check for confidence in the cardiac syncpulse (at step 690) as previously described. If confidence isestablished (at step 700), the cycle continues. If confidence is notestablished (at step 702), the user is informed (at step 704, forexample, by the heart turning yellow and flashing or turning solid red.

If the system 100 cannot determine acceptable confidence or no longerdetects a TTL pulse within a certain amount of time (e.g., about 10, 20,30, 40, 50, or 60 seconds), a timeout will be reached (at step 706), andthe user interface 150 can be used to notify the user (at step 708). Atthis time, the cycle can end, and any remaining packets would not bedelivered. The process then returns to start (at step 650). If thesystem can determine acceptable confidence (at step 700) within the settime limit, a timeout will not be reached (at step 688), and the cyclecontinues with continued monitoring of heart rate and checks forconfidence (at step 690), as previously described. If confidence isgained (at step 700), the next energy packet is delivered (at step 686).Once all packets are delivered, the treatment is deemed complete (atstep 710) and the user is informed of completion of treatment (at step708). If the current associated with delivery of any of the high energypackets (at step 686) exceeds a set value (e.g., about 45 amps), thecycle can also end (at step 708).

It may be appreciated that in some embodiments, components for acquiringthe electrocardiogram 170 are integrally formed with the generator 104.If the cardiac monitor is limited to acquiring up to a 5-lead ECG, andit may be beneficial to incorporate additional leads into the system.This would further eliminate the need to use the communications port 167to receive cardiac sync pulses. Rather, the processor 154 can beconfigured to defect the R-waves directly and to assess the integrity ofthe entire QRS complex.

In some embodiments, the processor 154 may be configured to use eitherfewer or more than five Δt's to calculate Δt-ave. In some embodiments,the processor 154 may be configured to use between three and ten Δt's tocalculate Δt-ave. Further, the processor 154 may be configured to use aΔt other than Δt6 and Δt7 to confirm confidence. For example, theprocessor 154 may be configured to use any subsequent Δt. The processor154 may also be configured to allow heart rates beyond the 40-150 bpmdescribed above. For example, the processor 154 may be configured toallow heart rates in the range of 30-160 bpm, including all values andsub ranges in between. The processor 154 may also be configured to allowΔt6 or other Δt7 to be more or less than ±10%. For example, theprocessor 154 may be configured to allow Δt6 or other data point,including rolling averages, to be within ±3% to ±50%. User interface 150examples provided herein are merely examples, and should not beconsidered limiting.

Thus, it may be appreciated that generator can be configured tocontinuously monitor the patient's heart rate, and in case cardiacarrhythmias are induced, the treatment will be automatically stopped andan alarm can sound.

VI. Imaging

Methods associated with imaging that can be useful include: (a)detecting diseased target tissue, (b) identifying areas to be treated,(c) assessing areas treated to determine how effective the energydelivery was, (d) assessing target areas to determine if areas weremissed or insufficiently treated, (e) using pre- or intra-proceduralimaging to measure a target treatment depth and using that depth tochoose a specific energy delivery algorithm to achieve tissue effects tothat depth, (f) using pre or intra-procedural imaging to identify atarget cell type or cellular interface and using that location or depthto choose a specific energy delivery algorithm to achieve tissue effectsto that target cell type or cellular interface, and/or (g) using pre-,intra-, or post-procedural imaging to identity the presence or absenceof a pathogen with or without the presence of inflamed tissue.

In some embodiments, confocal laser endomicroscopy (CLE), opticalcoherence tomography (OCT), ultrasound, static or dynamic CT imaging,X-ray, magnetic resonance imaging (MRI), and/or other imaging modalitiescan be used, either as a separate apparatus/system, orincorporated/integrated (functionally and/or structurally) into thepulmonary tissue modification system 100 by either incorporating intothe energy delivery catheter 102 or a separate device. The imagingmodality (or modalities) can be used to locate and/or access varioussections of tissue as demonstrated by a thick area of epithelium, gobletcell hyperplasia, submucosal glands, smooth muscle, and/or otheraberrancies relative to where the system is deployed in the chest. Insome embodiments, the targeted depth of treatment can be measured andused to select a treatment algorithm 152 sufficient to treat to thetargeted depth. At least one energy delivery body can then be deployedat the site of abnormal airway wall tissue and energy delivered toaffect the target tissue. The imaging modality (or modalities) can beused before, during, between, and/or after treatments to determine wheretreatments have or have not been delivered or whether the energyadequately affected the airway wall. If it is determined that an areawas missed or that an area was not adequately affected, the energydelivery can be repeated followed by imaging modality (or modalities)until adequate treatment is achieved. Further, the imaging informationcan be utilized to determine if specific cell types and or a desireddepth of therapy was applied. This can allow for customization of theenergy delivery algorithm for treating a wide variety of patientanatomies.

In some embodiments, imaging combined with the use of a fluorescentagent (e.g., fluorescein) can be performed to enhance recognition ofpathogens that may be in the airway. The fluorescent agent can be chosento directly tag certain pathogens (e.g., bacteria) or indirectly tagcells associated with various infections states (e.g., neutrophils),which will then be visible. In some embodiments, such an imagingmethod/approach can include the steps of gaining access to the airway,delivering the fluorescent agent to within the airway, exciting thefluorescent agent by delivering an excitation signal into the airway,and assessing the presence or absence of fluorescence in response to theexcitation signal.

A. Imaging for Access

In general, the methods, apparatuses, and systems disclosed herein canaccess pulmonary tissue or a target region (e.g., trachea, mainstembronchi, lobar bronchi, segmental bronchi, sub-segmental bronchi,parenchyma) via a natural orifice route (e.g., from the mouth or nose),an artificially created orifice (e.g., via a tracheotomy, via asurgically created stoma, and/or any suitable intra-operative and/orsurgical orifice), and/or via an artificially created orifice throughthe airway into other areas of the lung and/or tissue (e.g.,parenchyma). The type of approach utilized can depend on factors such asa patient's age, comorbidities, need for other concomitant procedures,and/or prior surgical history.

Methods for accessing the airway and/or other lung tissue (e.g.,parenchyma) can include using the working channel of a bronchoscopedelivered via the nose or month, into the trachea and/or more distalbronchi. As illustrated previously in FIGS. 8A-8B, a bronchoscope 112may be inserted in the mouth or oral cavity OC of the patient P or othernatural orifices such as the nose or nasal cavity NC. Similarly, otherlung tissue LT, such as parenchyma, may be accessed by via the nose ormouth, as illustrated in FIG. 22. As shown, the distal end of thecatheter 102 is advanced into the trachea T, the mainstem bronchi MB,and into the lobar bronchi LB crossing from an airway into thesurrounding lung tissue LT. This may be achieved with a tool or catheterhaving a guidance system which allows for guidance outside of the lungpassageway.

It may be appreciated that in some instances, direct visualization maynot be necessary and/or desired, and the treatment catheter can bedelivered directly into the airway via the nose or mouth.

In other embodiments, accessing the airway and/or lung tissue (e.g.,parenchyma) is achieved via other appliances inserted into the chest.Likewise, in some embodiments one or more of a variety of imaginemodalities (e.g., CLE, OCT) are used either along with directvisualization, or instead of direct visualization. As an example, abronchoscope 112 can be delivered via the mouth to allow for directvisualization and delivery of the catheter 102, while an alternateimaging modality can be delivered via another working channel of thebronchoscope 112, via the nose, or adjacent to the bronchoscope via themouth. In some embodiments, the imaging modality (e.g., directvisualization CLE, and/or OCT) is incorporated into the catheter 102with appropriate mechanisms to connect the imaging modality to eitherthe system generator 104 or commercially available consoles. FIGS. 23Aand 23B depict example images obtainable using CLE and OCT,respectively. These images can be used to guide delivery to apre-determined location previously identified on CT scan using airwaywall thickness (AWT) measurements, to target treatment based onvisualization of cell structures, and/or to assess the effectiveness oftreatment

B. Imaging for Treatment Planning

Methods associated with imaging can include using imagine pre-treatmentto plan the procedure. Imaging can be used for detecting diseased targettissue, identifying areas to be treated, and/or for determining theappropriate energy delivery algorithm to achieve a desired depth oftreatment. For example, a CT scan can be obtained preoperatively orintraoperatively, from which an AWT or Pil0 (theoretical airway wallthickness for an airway with an internal perimeter of 10 mm) measurementis obtained. Target zones can be identified using these metrics.Referring again to FIGS. 23A-23B, CLE or OCT can be used to measure atarget treatment depth. The desired treatment depth can be based uponthe thickness t of the epithelium E, as measured from the airway lumenLMN to the basement membrane BM; the distance d to a target cell typesuch as goblet cells GC or smooth muscle (not shown), and/or any otherstructure that the physician determines to be medically appropriate.FIG. 23B provides an example OCT image of a diseased airway. Thethickness t′ of the airway can be determined by measuring the distancefrom the airway lumen LMN to the outer edge EDG of the airway. Thosemeasurements can then be used to choose a specific energy deliveryalgorithm 152 to achieve tissue effects to that depth. For example, thegenerator 104 can have a user interface 150 (such as a touch screen)that allows the selection of desired treatment depth. Once the operatorchooses the desired depth, the system 100 can be configured toautomatically select the appropriate energy delivery algorithm 152 toachieve that depth. Other anatomical assessments can also be made tohelp select target treatment sites. For example, using CLE, one canassess the size and/or density of goblet cells GC along with thedistance d from the airway lumen LMN to the goblet cells GC to targetboth a treatment location and a target depth. These methods would allowfor the therapy to be customized to each patient.

In some embodiments, the use of the bronchoscope 112 may allow forpre-procedural planning, wherein a sputum sample is acquired foranalysis. If one or more pathogens are found, this information may befor determining the appropriate energy delivery algorithm 152 to achievea desired depth of treatment as a consequence of the initial data. Insome cases, such as the combination of pathogen identification inconjunction with improved tissue imaging, it may be desirable to limitthe treatment depth to merely the mucus layer M, where pathogens thrive;whereas, in other cases, it may be desirable to affect deeper airwaystructures. For planning the treatment, a sputum sample may be obtainedand assessed to determine if an infection of the tracheobronchial treemay be present. If an infection is deemed to be present, the generatorcan be programmed to affect the mucus layer of the airway withoutsubstantially impacting other layers, which contains the pathogenscausing the infection, or other pulmonary tissues. The method ofperforming sputum testing can also be used to assess the effect of thetreatment. For assessing the effect of the treatment, additional sputumsamples, as well as biopsies, can be taken following the energy-deliveryprocedure or at a later time. By comparing these samples and biopsies tothe planning samples and each other, the effectiveness of the procedurecan be determined. These data, combined with a clinical examination ofthe patient, can be used to further optimize therapy.

The method of performing on or more tissue biopsies can be used to plantreatment and/or assess the effect of the treatment. For planning thetreatment, a biopsy can be performed and assessed microscopically todetermine patient suitability (e.g., excessive mucus production, gobletcell density, goblet cell hypertrophy, epithelial thickness,inflammation, basement membrane thickening, submucosal inflammation,submucosal eosinophilia, submucosal gland thickening, smooth musclehypertrophy, or other parameters) and/or degree of airway obstruction(e.g., thickness of epithelial and/or other layers). By measuring one ormore of these parameters, the generator can be programmed to affect acertain depth of tissue, allowing for customization of theenergy-delivery algorithm for each patient. For example, voltage can beincreased for patients with thicker epithelial layers. For assessing theeffect of the treatment, additional biopsies can be performedimmediately following the energy-delivery procedure or at a later time.By comparing these biopsies to the planning biopsy and each other, theeffectiveness of the procedure can be determined. For example, if thepost treatment biopsy showed no change from the planning biopsy, eitherthat location was not treated or insufficient energy was applied toaffect the tissue. But, if the post treatment biopsy showed a reductionin epithelial thickness and/or structure (i.e., regeneration of healthyepithelium), the effectiveness of the energy delivery can be verified.By performing multiple biopsies along the airway, one could furtherassess whether or not a sufficient percentage of the total surface areawas treated. These data, combined with a clinical examination of thepatient can be used to further optimize therapy.

C. Imaging During Treatment

Use of a bronchoscope 112 allows for direct visualization of the targettissues and visual confirmation of catheter 102 placement anddeployment. In some embodiments, direct visualization may not benecessary and the catheter 102 is delivered directly into the airway.Alternatively, a variety of imaging modalities (e.g., CLE, OCT) can beused either along with direct visualization or instead of directvisualization. As an example, a bronchoscope 112 can be delivered viathe mouth to allow for direct visualization and delivery of the catheter102, while an alternate imaging modality can be delivered via anotherworking channel of the bronchoscope 112, via the nose, or adjacent tothe bronchoscope via the mouth. In some embodiments, the imagingtechnology (e.g., direct visualization, CLE, and/or OCT) can beincorporated into the catheter with appropriate mechanisms to connectthe imaging technology to either the system generator or commerciallyavailable consoles.

D. Imaging Post Treatment

In some embodiments, methods associated with imaging can include usingimaging (e.g., using the imaging modality 169) to assess theeffectiveness of the procedure intra-operatively and/or post procedure.In some embodiments, during the procedure, the operator can use imagingto assess target treatment areas to determine if areas were missed orinsufficiently treated. For example, if an area was insufficientlytreated, the operator can observe that the target depth was notachieved. The operator can then re-measure the depth, select anappropriate treatment algorithm 152, and treat again in the samelocation. In some embodiments, if the generator 104 does not have avariety of pre-set algorithms based on desired depth, the same energydelivery algorithm can be used. Imaging can be also used post procedureto monitor the healing process and correlate tissue changes to clinicaloutcomes. The healing process can make it easier to visualize tissuechanges and assess the effectiveness of the procedure. These data canfurther lead to the physician deciding to perform additional proceduresto affect additional tissue.

VII. Catheter Embodiments

A variety of energy delivery catheter 102 embodiments are envisioned.Characteristics and features described herein can be used in anycombination to achieve the desired tissue effects. Typically, suchcatheters 102 are sized and configured to treat lung passageways havinga lumen diameter of approximately 3-20 mm. Typically, energy deliverybodies 108 expand within the lung passageway lumen so as to reside near,against, in contact, or exerting pressure or force against the wall W ofthe lumen. In some embodiments, the energy delivery body 108 expands toa diameter of up to 22 mm, particularity 3-20 mm or 3-22 mm.

FIG. 24 depicts an embodiment of an energy delivery catheter 102 havinga single energy delivery body 108 comprised of at least two protrusions,each protrusion extending radially outwardly so as to contact an innerluminal wall of a lung passageway. It may be appreciated that although asingle protrusion may be present, typically two protrusions are presentto apply substantially opposing forces to the wall of the lungpassageway to support the catheter therebetween. In this embodiment, theat least two protrusions comprise a plurality of ribbons or wires 120which are constrained by a proximal end constraint 122 and a distal endconstraint 124 forming a spiral-shaped basket. In this embodiment, theproximal end constraint 122 is attached to a shaft 106, and the shaft106 does not pass through the energy delivery body 108. This allows theenergy delivery body 108 to collapse upon itself without having theadded dimension of the shaft 106 therein. The energy delivery body 108is delivered to the targeted area in a collapsed configuration. Thiscollapsed configuration can be achieved, for example, by placing asheath 126 over the energy delivery body 108. In FIG. 24, since theshaft 106 terminates at the proximal end constraint 122, the distal endconstraint 124 is essentially unconstrained and free to move relative tothe shaft 106 catheter 102. Advancing a sheath 126 over the energydelivery body 108 allows the distal end constraint 124 to move forward,thereby lengthening/collapsing and constraining energy delivery body108. Retraction of the sheath 126 allows the energy delivery body 108 toexpand, such as through self-expansion. It may be appreciated that in analternative embodiment, the ribbons or wires 120 are straight instead offormed into a spiral-shape (i.e., configured to form a straight-shapedbasket). In still another embodiment, the energy delivery body 108 islaser cut from a tube.

In some embodiments, the energy delivery body 108 comprises a pluralityof electrodes 107, wherein each wire 120 acts as a separate electrode107 and is able fire separately using the wire next to it as a returnelectrode or using a dispersive electrode attached to the patient as areturn electrode. In some instances, each wire 120 of the energydelivery body 108 can be electrically isolated from each other wire 120,and separate conductor wires can transmit the energy from the generator104 to the wires 120 of the energy delivery body 108. In otherinstances, two or more wires 120 can be electrically connected to oneanother to form one or more sets of wires. The algorithm 152 of thegenerator 104 can perform the appropriate switching from one wire (orset of wires) to another as well as the alternation of the wire'sfunction between active and return (ground) states.

FIG. 25 depicts an embodiment wherein the energy delivery catheter 102includes two energy delivery bodies, a first energy delivery body 108and a second energy delivery body 108′, wherein each body 108, 108′functions similarly to the embodiment of FIG. 24. In this embodiment,the first energy delivery body 108 is disposed along a distal end of afirst shaft 106 and the second energy delivery body 108′ is disposedalong a distal end of second shaft 106′. As shown, the shafts 106,106′are aligned in parallel so that together they are passable through asheath 126. In some embodiments, the shafts 106, 106′ are fixed togetherso that they move in unison. In such embodiments, the shafts 106, 106′are typically arranged so that the energy delivery bodies 108, 108′ arestaggered, such as having the second energy delivery body 108′ disposedmore distally than the first energy delivery body 108, as shown in FIG.25. In such arrangement, the energy delivery bodies 108, 108′ may beseparated by any suitable distance. Likewise, the energy bodies 108,108′ are arranged in relation to the shafts 106, 106′ so that expansionof the energy bodies 108, 108′ are not impinged by in any way. Forexample, in this embodiment, the energy delivery bodies 108, 108′ arearranged so that the second shaft 106′ does not interfere with theexpansion of the first energy delivery body 108. Rather, the secondshaft 106′ passes through the basket-shaped energy delivery body 108,between the wires 120. In some embodiments, the shafts 106, 106′ are notfixed together and are able to move in relation to each other, inparticular the shafts 106, 106′ are able to slide longitudinally inparallel to each other. In such embodiments, the shafts 106, 106′ may bemoved in relation to each other to increase or reduce the distancebetween the energy delivery bodies 108, 108′. Once a desired distance isachieved, the shafts 106, 106′ may be fixed in place to maintain thedesired distance between the energy delivery bodies 108, 108′.

In the embodiment illustrated in FIG. 25, each energy delivery body 108,108′ is comprised of a spiral-shaped basket made up of electrodes 107 inthe form of wires 120. The energy delivery bodies 108, 108′ can beactivated in a bipolar fashion and/or a monopolar fashion. It may beappreciated that in alternative embodiments, the wires or ribbons 120can be straight instead of formed into a spiral-shape (i.e., configuredto form a straight-shaped basket). In some embodiments, the energydelivery bodies 108, 108′ are laser cut from a tube. The thisembodiment, the first shaft 106 terminates at the first proximal endconstraint 122 of the first electrode body 108, leaving the first distalend constraint 124 essentially unconstrained. The second shaft 106′terminates at a second proximal end constraint 122′ of the secondelectrode body 108′ leaving the second distal end constraint 124′essentially unconstrained. Advancing a sheath 126 over the energydelivery bodies 108, 108′ allows the distal end constraints 124, 124′ tomove forward, thereby collapsing, lengthening and constraining theenergy delivery bodies 108, 108′. Retraction of the sheath 126 exposesthe energy delivery bodies 108, 108′ for expansion and delivery ofenergy.

FIG. 26 depicts an embodiment of an energy delivery catheter 102 havinga single energy delivery body 108 comprised of a monopolar electrode 107formed by a plurality of ribbons or wires 120, wherein the energydelivery body 108 is mounted on a shaft 106 which extends through theenergy delivery body 108. Again, the energy delivery body 108 has abasket shape constrained by a proximal end constraint 122 and a distalend constraint 124. In this configuration, in order for the energydelivery body 108 to collapse, either the proximal end constraint 122 ordistal end constrain 124 slide freely on the shaft 106 while the otherend is fixedly attached to the shaft 106. Upon the delivery of theenergy delivery body 108 to the target treatment area, the sheath 126 iswithdrawn by the operator via, for example, a lever or slider or plungerof the catheter's handle 110, which is operatively connected to thesheath 126. The withdrawal of the sheath 126 removes the restraintkeeping the energy delivery body 108 collapsed, thus allowing itsexpansion leading to the wires 120 of the energy delivery body 108contacting the bronchial wall.

In some embodiments, the collapsed configuration of the energy deliverybody 108 can be achieved by mechanisms which restrict its expansionwithout the use of a sheath 126. For example, in some embodiments, apull wire is attached to the proximal end constraint 122 of the energydelivery body 108 and extends down a lumen along the shaft 126 where itis operatively connected to a lever, slider, or plunger of thecatheter's handle 110. In this embodiment, the distal end constraint 124is fixedly attached to the shaft 106 and the proximal end constraint 122is configured to slide freely on the shaft 106. While the pull wire isunder pull force, the proximal end constraint 122 is positioned so thatthe energy delivery body 108 is collapsed. The pull wire can bemaintained in this position by restraint within the handle 110. Releaseof the pull force, such as by reduction or removal of the restraintwithin the handle 110, allows the pull wire to move, thus freeing theproximal end constraint 122 and allowing it to travel closer to itsdistal end constraint 124 as self-expanding properties of the energydelivery body 108 cause expansion.

In other embodiments, the proximal end constraint 122 is affixed to theshaft 106 and the distal end constraint 124 is free to slide on theshaft 106. Further, a push rod (or tubing to achieve higher columnstrength) is attached to the distal end constraint 124 and extends downa lumen along the inner shaft 106 where it is operatively connected tomechanism such as a lever, slider, or plunger of the catheter's handle110. When the push rod is pushed and subsequently restrained within thehandle 110 of the catheter 102, the distal constraint 124 is moved awayfrom the proximal end constraint 122 which causes the energy deliverybody 108 to collapse. When the energy delivery body 108 isself-expanding, release of the push rod allows the energy delivery body108 to expand. Alternatively, the push rod may be retracted, pulling thedistal end constraint 124 toward the proximal end constraint 122 whichcauses the energy delivery body 108 to expand.

In the embodiment shown in FIG. 26, the energy delivery body 108 isformed b a braided metal tube constrained at both the proximal endconstraint 122 and the distal end constraint 124 and configured to forma basket. The energy delivery body 108 can be controlled (i.e.,collapsed, deployed) as described above. When the energy delivery body108 comprises a braided metal tube, each wire in the braided tube issupported by multiple wires next to it as well as by the interwovennature of the braid itself. This support and interwoven configurationcan assure minimal variation in space between wires, otherwise known aspore or opening size of the braid. In addition, this support andinterwoven configuration can allow constructing the braided tube fromvery small wires and yet have significant radial stability of thebasket. This allows the use of many wires (e.g., 12, 16, 18, 20, 22, 24,etc.) while maintaining a relatively small profile of the energydelivery body 108 in the collapsed/constrained state and optimizing theopening size of the braided tube when electrode(s) is/aredeployed/expanded. In this embodiment, the space between wires is rathersmall, leading to a treatment that is essentially continuous over 360degrees of the inner lumen of a lung passageway.

FIG. 27 illustrates an embodiment wherein both energy delivery bodies108, 108′ are carried on a single shaft 106. In order for the energydelivery bodies 108, 108′ to collapse, the first proximal end constraint122 of the first energy delivery body 108 is fixedly attached to thecatheter shaft 106. The other end constraints 122′, 124, 124′ are ableto slide freely on the catheter shaft 106. The catheter is deliver witha sheath 126 constraining the energy delivery bodies 108, 108′. Upondelivery of the energy delivery bodies 108, 108′ to the target area, thesheath 126 can be withdrawn by the operator via, for example, amechanism such as a lever or slider or plunger of the catheter's handle110. The withdrawal of the sheath 126 removes the restraint keepingenergy delivery bodies 108, 108′ collapsed, thus allowing theirexpansion leading to the surfaces of the energy delivery bodies 108,108′ contacting the bronchial wall. In addition, in some embodiments,the first distal end constraint 124 and the second proximal endconstraint 122″ are connected to each other via coupler 800. The coupler800 is constructed using an electrically insulative material (e.g.,polyether block amide (Pebax®) tubing, polyimide tubing, etc.) toprovide an insulative gap 802 between energy delivery bodies 108, 108′to achieve electrical discontinuity between them. In some embodiments,this gap 802 is between 1 and 20 mm. This prevents arcing within thecatheter shaft 106.

In some embodiments, the collapsed configuration of the energy deliverybodies 108, 108′ can be achieved by restricting their expansion withoutthe use of a sheath 126. For example, in one embodiment the distal endof a pull wire (not shown) is attached to the second distal endconstraint 124′ and the proximal end of the pull wire is attached to amechanism of the handle 110 (for example plunger, slider or lever). Thefirst proximal end constraint 122 is fixedly attached to the cathetershaft 106 and the other end constraints 124, 122′, 124′ slide freelyover the catheter shaft 106. Such a configuration assumes that energydelivery bodies 108, 108′ are in a collapsed configuration prior toinitiating placement via a bronchoscope and require the operator todeploy/expand them. This deployment/expansion is achieved by theoperator activating the mechanism of the handle 110 (e.g., lever,plunger or slider) which pulls the second distal end constraint 124′toward the first proximal end constraint 122, thus effectivelydeploying/expanding both energy delivery bodies 108, 108′. In anotherconfiguration, expansion can be achieved by employing two pull wires,one attached separately to each energy delivery body 108, 108′. In suchembodiments, the operator can control the level of expansion of theenergy delivery bodies 108, 108′ separately.

In some embodiments, the one or more energy delivery bodies 108, 108′are not constrained at both ends, rather one end is unconstrainedcreating a half-basket shape. FIG. 28A illustrates an embodiment whereinone energy delivery body energy 108′ is unconstrained at one end forminga half-basket shape when expanded. In this embodiment, both the energydelivery bodies 108, 108′ are comprised of braided metal wires. Thedistal-most energy delivery body 108′ is constrained at both the secondproximal end constraint 122′ and the second distal end constraint 124′and configured to form a closed braided basket shape. The distal-mostenergy delivery body 108′ is expandable so that typically at least thewidest expansion diameter contacts the wall W of the lung passageway.The most proximal or first energy delivery body 108 is constrained at afirst proximal end constraint 122 and configured to form anapproximately half-open basket or half-basket shape when expanded, asshown. The proximal energy delivery body 108 is expandable so thattypically at least the widest expansion diameter contacts the wall W ofthe lung passageway. The shaft 106 is fixedly attached to the first andsecond proximal end constraints, 122, 122′. The half basket shape of theproximal energy delivery body 108 allows its widest expansion diameterto be closer to that of the distal-most energy delivery body 108′ thanwould otherwise be the case if the proximal energy delivery body 108were whole shaped. Decreasing this distance between the energy deliverybodies 108, 108′ allows for a treatment effect between the energydelivery bodies 108, 108′ in addition to at the energy bodies 108, 108′.This ultimately creates a larger surface treatment effect given theeffect between the bodies 108, 108′. In addition, the half basket shapemay help avoid arcing.

The configuration depicted in FIG. 28A is delivered with the use of asheath (not shown) as described in detail above, wherein both energydelivery bodies 108, 108′ are self-expandable. In another embodiment,the second energy delivery body 108′ is placed in a collapsed stateprior to delivery into a bronchoscope and once positioned in a desiredtarget area, deployed/expanded via a pull wire (not shown) connected toits second distal end constraint 124′) and to a mechanism in the handle110. This combination of full-basket (energy delivery body 108′) andhalf-basket (energy delivery body 108) can be employed for bipolar ormonopolar energy delivery. When electrodes are made of a braided metalwires, each wire is supported by multiple wires next to it as well as bythe interwoven nature of the braid itself. This support and interwovenconfiguration can assure minimal variation in space between wiresotherwise known as pore or opening size of the braid. In addition, thissupport and interwoven configuration allow constructing the braid fromvery small wires and yet have significant radial stability of thebasket. This allows the use of many wires (for example 12, 16, 18, 20,22, 24, etc.) while maintaining small profile of the energy deliverybodies 108, 108′ in a collapsed or constrained state while optimizingthe opening size of the braid when the energy delivery bodies 108, 108′are deployed or expanded. In this embodiment, the space between wires israther small, leading to a treatment that is 360 degrees within a lungpassageway.

FIG. 28B illustrates an embodiment wherein both the energy deliverybodies 108, 108′ are comprised of braided metal wires with the proximalend constraints 122, 122′ affixed to the shaft 106. In this embodiment,both energy delivery bodies 108, 108′ are configured to formhalf-baskets. This configuration is sheath (not shown) may be deliveredwith the use of a sheath as described above, wherein the energy deliverybodies 108, 108′ are self-expandable. This configuration of half-basketenergy delivery bodies 108, 108′ can be employed for bipolar and/ormonopolar energy delivery.

In some embodiments, the entire surface of the one or more energydelivery bodies 108 is energized by the energy signal for delivery tothe target tissue. However, in other embodiments, an active surface areaof the energy delivery body 108 is provided wherein the remainingportions are not active. In some embodiments, this is achieved bypartially insulating one or more portions of the energy delivery body108 leaving one or more active region(s). For example, FIG. 29illustrates a braided wire basket energy delivery body 108 comprised ofenergizable wires 120 (acting as one or more electrodes) wherein some ofthe wires 120 are insulated with portions of the insulation removed todefine an active area 820. In some embodiments, the insulation isremoved from the outer (tissue contacting) surface of the wire 120. Thisapproach can be useful, for example, if the measured impedance via theelectrode wire 120 is affected by the amount of the exposed metal and ifit is desirable for the measured impedance to represent theelectrode-to-tissue interface. In other embodiments, the insulation canbe removed on both the outer and inner surfaces of the electrode wire120. One method for manufacturing an energy delivery body 108 with thisconfiguration involves creating a braid using insulated wires, thenusing appropriate means (e.g., laser, mechanical) to remove theinsulation to create one or more active areas 820. While this exampledepicts a single active area 820, a plurality of active areas is alsoenvisioned in order to generate any treatment pattern. Similartechniques can also be employed for non-braided energy delivery bodies108 described herein. In these embodiments, the insulation can beapplied or removed as part of the manufacturing process to define anyactive area (or areas) 820 configuration desired to achieve varioustreatment patterns.

FIG. 30 illustrates another embodiment wherein a metal (e.g. Nitinol)tube 830 is laser cut to form a collapsed basket 832 with both endsconstrained via the tube 830 itself. The basket 832 can then be expandedand shape set, such that it can self-expand during use, so as to performas the energy delivery body 108. Alternatively, push/pull mechanisms canbe employed to expand/collapse the basket 832 for delivery andtreatment. In some embodiments, one end 834 of the basket 832 is removedto create free ends 836, as illustrated in FIG. 31. Insulation (e.g.,polymer tubing) can then be advanced over the free ends 836 and appliedto portions of the basket 832. In some embodiments, the insulation isapplied to proximal and distal portions of the basket, leaving one ormore conductive/active areas 820 therebetween. In other embodiments, asshown in FIG. 31, the wires 120 of the basket 832 are insulated and oneor more separate additional electrodes 840 (shown as coils) areconnected to the insulated basket wires to form active areas 820. Thisassembly can then be affixed to a catheter 102 such that the energydelivery body 108 can be activated as a monopolar electrode withmultiple pre-defined active areas 832.

FIG. 32 illustrates another embodiment of an energy delivery body 108.In this embodiment, the body 108 comprises a plurality of tines 840,similar to the free ends 836 of FIG. 31. The tines 840 are able toexpand outwardly so as to contact the lung passageway wall. In someembodiments, one or more of the tines 840 are insulated with insulationmaterial 842. Electrodes 107 disposed along each tine 840, such as nearthe distal ends of each tine 840, can be created by removal of theinsulation material 842 to expose an underlying energizable element orwire. Alternatively, a separate electrode 107 may be mounted on theinsulation material 842, as depicted in FIG. 32. In some embodiments,the tines 840 are formed of polymer-covered wires, wherein the wire canact as structural support to self-expand the tines 840, can beenergizable to deliver treatment energy and/or can be used to sensetemperature and/or impedance. In some embodiments, the tines 840 arecollapsible via a sheath 126 for delivery and allowed to expand intocontact with the tissue upon retraction of the sheath 126. Theelectrodes can all fire simultaneously in a monopolar fashion, can fireindependently in a monopolar fashion, and/or fire between one another inany pattern necessary to generate the desired treatment effect. Thelength of the electrodes can range from about 3 mm to about 5 cm, suchas 3 mm, 5 mm, 1 cm, 2 cm, 3 cm, 4 cm or 5 cm. While depleted as all thesame size in FIG. 32, the size (e.g., length, width) can vary.

FIG. 33 illustrates another embodiment of an energy delivery body 108.In this embodiment, the energy delivery body 108 comprises one or moreprotrusions 850 rather than a basket weave. Each protrusion 850 isformed by a wire or ribbon 120 which acts as an electrode and bendsradially outward from the longitudinal axis or shaft 106 of the catheter102. In this embodiment, each protrusion 850 is electrically isolatedfrom each of the other protrusions. The protrusions 850 may be comprisedof a variety of suitable materials so as to act as an electrode, such asstainless steel, spring steel, or other alloys, and may be, for example,round wires or ribbon. Each protrusion 850 is insulated with a segmentof insulation 852, such as a polymer (e.g., PET, polyether block amide,polyimide), over at least a portion of the proximal and distal ends ofthe energy delivery body 108. The exposed portion 854 of the wire orribbon can then act as an electrode on each protrusion 850. In oneembodiment, the exposed portions 854 of the protrusions 850 arecompletely free of insulation 832. In another embodiment, the insulation852 is removed only from the outer surface of the protrusion 850 leavingthe side of the protrusion 850 that does not come in contact with thetissue (e.g., an inner surface that faces the shaft 106 of the catheter102) completely insulated. In one embodiment, each protrusion 850 isenergized independently, with two protrusions 850 acting as neutralelectrodes (return) and two protrusions 850 acting as active electrodes.Neutral and active electrodes can be positioned right next to eachother. Neutral electrodes located 180 degrees from each other (oppositeelectrodes) can be electrically connected to each other and so can bethe active electrodes. In this embodiment, only two conductive wires(power lines) are needed to connect two pairs of protrusions 850 to thegenerator 104. Further, pairs of protrusions 850 that are utilized in abipolar fashion can further be multiplexed to allow for any combinationor rotation of active versus neutral electrode. The generator 104 can beconfigured to have sufficient channels to support any of theseapproaches (i.e., 1 to 4 channels). This embodiment of the energydelivery body 108 can optionally be delivered in a collapsedconfiguration and expanded into tissue contact via a pullback wire andmechanism within the handle.

FIG. 34 illustrates another embodiment of energy delivery body 108comprising one or more protrusions 850 wherein each protrusion 850 bendsradially outward from the longitudinal axis or shaft 106 of the catheter102. However, in this embodiment, each protrusions 850 is formed from anon-conductive material and carries, supports, and/or is otherwisecoupled to a separate electrode 107. Each electrode 107 has a conductivewire 860 connecting the electrode 107 to the generator 104. Theprotrusions 850 position said electrodes 107 against the tissue uponexpansion, such as via a pull wire and mechanism within the handle. Inthis embodiment, each electrode 107 is placed over or adjacent eachprotrusion 850. If the protrusions 850 are comprised of a metal,insulation is provided to electrically isolate the electrodes 107 fromthe protrusions 850 themselves. If the protrusions 850 are comprised ofa polymer or other non-conductive material, additional insulation wouldnot be required. In some embodiments, the protrusions 850 are comprisedof round wire or ribbon and configured to form a straight basket, asshown. In other embodiments (not shown), the protrusions 850 areconfigured in a spiral shape. It may be appreciated that separateelectrodes 107 as depicted in FIG. 34 may likewise be applied to otherembodiments, such as wherein the basket is comprised of a braidedmaterial. Similar to the embodiment of FIG. 33, each electrode 107 maybe energized in a variety of combinations. Furthermore, each protrusions850 can carry the electrodes 107 that can be electrically connected toeach other or electrically insulated from each other. To increase thesurface area of the electrodes 107 each can be constructed from, forexample, a metallic coil or in a form of a slotted (e.g. laser cut)tube. These configuration would allow for greater spatial coverage andyet maintain the flexibility of the electrodes 107 to allow theprotrusions 850 of the basket to bend and straighten freely. As in FIG.33, the surface of the protrusions 850 can be completely exposes orinsulated over areas that do not come in contact withe the tissue.

FIG. 35 illustrates another embodiment of a catheter 102 having at leastone energy delivery body. In this embodiment, each energy delivery bodycomprises an expandable coil that can either act an electrode itself orcan act as a carrier for separate electrodes mounted thereon. In thisembodiment, the catheter 102 comprises two energy delivery bodies, afirst energy delivery body 108 which is disposed proximally to a secondenergy delivery body 108′. Each energy delivery body 108, 108′ has theshape of an expandable coil. A distal end 870 of the second energydelivery body 108′ is coupled with or formed to an inner member 872, andproximal end 874 of the first energy delivery body 108 is coupled withan outer member 876. The outer member 876 is rotatable relative to theinner member 872 to collapse and/or expand the energy delivery bodies108, 108′. A coupler 878 attaches the energy delivery bodies 108, 108′together and provides insulation between them, if desired. The energydelivery bodies 108, 108′ can be activated in a monopolar and/or bipolarfashion. The size of the energy delivery bodies 108, 108′ can be thesame or different, as described herein. The length of each expanded coilcan range from about 5 mm to about 20 mm.

FIG. 36 depicts an energy delivery body 108 configured for more limitedapplication of treatment energy, such as in a narrow region along thelung passageway wall or along a partial inner circumference of the lungpassageway. In this embodiment, the energy delivery body 108 comprises acoil that limits the length of the active area. Such embodiments can beemployed if very focal tissue effects are desired or if tissue effectsextend beyond the active area in contact with tissue. In the embodiment,the energy delivery body 108 comprises a coil 880 having a width and alength, wherein the length of the coil 880 can be pre-shaped into asemi-circular or circular pattern, as shown. The treatment length L1 isprovided by the width of the coil 880 as it contacts the lung passagewaywall W. This configuration can be activated in a monopolar configurationas depicted; however, it is further envisioned that two or more coils880 can be employed to allow for bipolar and/or multiplexed energydelivery. Similarly, FIG. 37 illustrates an embodiment of an energydelivery body 108 comprising a rod 882 (such as shaft 106) having awidth and a length, wherein the length of the rod 882 is pre-shaped intoa semi-circular or circular pattern, as shown. The rod 882 includes oneor more electrodes 107 disposed along its length. The one or moreelectrodes 107 may be embedded into or otherwise affixed to the rod 882.The treatment length L1 is provided by the width of the one or moreelectrodes 107 which contact the lung passageway wall W. This embodimentallows for monopolar activation between all electrodes and a dispersive(neutral) electrode, bipolar activation between individual electrodes,and/or multiplexed activation between any combination of electrodes. Itis further envisioned that two or more of these devices can be employedto allow for energy delivery between them. When the energy deliverybodies 108 are pre-shaped into the semi-circular or circularconfiguration, a sheath 126 can be used to collapse and constrain theenergy delivery body 108 for self-expansion and/or a pull/push wire canbe used to expand the energy delivery body 108. These methods forexpanding and/or collapsing an energy delivery bodies 108 are describedin detail within other examples provided.

The energy delivery body 108 can be optimized for situations in whichforce exerted onto the bronchial wall is desired to be more highlycontrolled. In this embodiment, the energy delivery body 108 isdelivered into the bronchial lumen via a three-step process. First, asillustrated in FIG. 38, a sheath 126 is withdrawn proximally thusexposing one or more prongs 900 which act as protrusions. Thisembodiment includes four prongs 900 arranged symmetrically around acentral lumen 902, as illustrated in the cross-sectional illustration ofFIG. 38A. It may be appreciated that any number of prongs 900 may bepresent including one, two, three, four, five, six or more. Each prong900 includes at least one electrode 107. FIG. 39 illustrates anembodiment of a prong 900 having two electrodes 107 having an elongateshape (such as wire) attached to an insulating substrate 904, such as apolymer substrate (e.g. ribbon, strip), therebetween as a means tomaintain distance between the electrodes 107. It may be appreciated thatthe electrodes 107 may have a round or square/rectangular cross-section,and are typically affixed to the insulating substrate 904 such that theelectrodes 107 are substantially parallel to one another. Themanufacturing method of attaching the electrodes 107 to the insulatingsubstrate 904 can employ (but is not limited to) co-extrusion,deposition, adhesive based bonding, and thermal bonding. The width ofthe insulting substrate 904 can vary.

FIG. 40 illustrates an embodiment of a prong 900 having a narrowerinsulating substrate 904 than depicted in FIG. 39. Likewise, FIG. 41illustrates an embodiment of a prong 900 having yet narrower insulatingsubstrates 904 and greater than two electrodes 107. In particular, FIG.41 illustrates five electrodes 107, however it may be appreciated thatany number of electrodes 107 may be present, such as one, two, three,four, five, six, seven, eight or more. FIG. 42 illustrates a pluralityof electrodes 107 mounted on a polymer substrate (e.g., ribbon, strip)wherein the electrodes 107 have an elongate shape (such as wire) and arepositioned substantially in parallel to each other leaving a gap betweeneach wire.

In some embodiments, the insulating substrate 904 with electrodes 107 isconfigured as a strip (FIGS. 39-42). Thus, the electrodes 107 aredeployed as a linear strip positioned along a length of an airway. Inother embodiments, the insulating substrate 904 with electrodes 107 isconfigured as a helix wherein the electrodes are deployed in a helicalfashion. FIG. 43 illustrates the insulating substrate 904 withelectrodes 107 as shown in FIGS. 39-40 configured as a helix. FIG. 44illustrates the insulating substrate 904 with electrodes 107 shown inFIG. 41 configured as a helix.

In some embodiments, a push-pull mechanism as described previously inrelation to other embodiments can be employed to deploy the strip orribbon. In case of the helix, the rotational mechanism can also be used.Electrodes 107 can be electrically connected to each other, can beinsulated from each other or different patterns of electricalinterconnection between electrodes depending on the energy applicationalgorithm controlled by the generator.

Once the one or more prongs 900 are exposed, the second step of thethree-step process involves introducing an expandable member 910, suchas a balloon, by advancing the expandable member 910 from the lumen 902while in an unexpanded state. The third step involves expanding theexpandable member 901, such as inflating the balloon, as illustrated inFIGS. 45A-45B, until a desired interface between the prongs 900 (andtherefore electrodes 107) and bronchial wall W is achieved. In anotherembodiment, the prongs 900 are positioned while the expandable member910 is already disposed beneath the prongs 900 so their relativelongitudinal position does not change. In this configuration, thewithdrawal of the sheath 126 exposes both the expandable member 910 andthe prongs 900 at the same time, thus eliminating the step of advancingthe expandable member 910 out of the lumen 902. As described above, theexpandable member 910 is subsequently expanded (e.g. inflated) until thedesired interface between the prongs 900 and bronchial wall S isachieved. The size (e.g. length, width) of the prongs 900 can be thesame or different. The number of prongs 900 can vary between 1(monopolar configuration) and 100 (monopolar and/or bipolar)configuration. Energy application to the electrodes 107 can vary widelydepending on the algorithm of the energy delivery apparatus (e.g.generator).

FIG. 46 illustrates an embodiment of an energy delivery catheter 102with more than two energy delivery bodies 108 (four energy deliverybodies 108 are shown) activatable in a bipolar/multiplexed fashion. Inthis embodiment, the energy delivery bodies 108 are comprised of braidedmetal wires, wherein the wires serve as electrodes. Energy deliverybodies 108 can be activated in a bipolar fashion by cycling the powersupplied by an external generator 104 between any pair of two energydelivery bodies 108, one of which is neutral. The combination betweenactive and neutral energy delivery bodies 108 can be varied as well. Forexample, in one embodiment the energy can be applied to two or moreenergy delivery bodies 108 while one energy delivery body 108 serves asa neutral electrode. The combination of active energy delivery bodies108 and neutral energy delivery bodies 108, the switching/cycling of theenergy between active and neutral energy delivery bodies 108, the choicebetween activated and deactivated energy delivery bodies 108 is achievedthrough the energy delivery algorithm 152 of the generator 104. Thealgorithm 152 can apply and distribute energy between energy deliverybodies 108 based on a pre-defined approach, imaging data, and otherfactors determining the desired area and depth of treatment.

FIG. 47 illustrates another embodiment of an energy delivery catheter102 having a multi-energy delivery body design. In this embodiment, theenergy delivery bodies 108 are activated in a monopolar and/or bipolarmultiplexed fashion. Monopolar energy delivery can be achieved bysupplying energy between one or more energy delivery bodies 108positioned near the distal end 920 of the catheter 102 and a dispersive(return) electrode 922 applied externally as the skin of the patient P.The combination of active energy delivery bodies 108, theswitching/cycling of the energy between the active energy deliverybodies 108 and the dispersive electrode 922, and the choice betweenactivated and non-activated energy delivery bodies 108 is achievedthrough the energy delivery algorithm 152 of the generator 102. Thealgorithm 152 can apply and distribute energy between energy deliverybodies 108 based on a pre-defined approach, imaging data and otherfactors determining the desired area and depth of treatment.

It may be appreciated that many of the figures herein depict energydelivery bodies 108 of essentially the same size (e.g., length,diameter) and shape for illustrative purposes, and should not beconsidered limiting. In some embodiments, the energy delivery bodies canvary in size in order to account for tapering of the airway lumen,better localize the energy field, and/or enhance treatment of thetissue. For example, if the desired catheter placement resumes a distalenergy delivery body to be in the lobar bronchi (about 9 mm-12 mm indiameter) and a proximal energy delivery body to be in the mainstembronchi (about 12 mm-16 mm in diameter), the distal energy delivery bodycan be designed to expand to about 12 mm and the proximal energydelivery body to expand to about 16 mm. The energy delivery bodies canalso be of different sizes to better localize the energy field. Forexample, if monopolar energy delivery is desired, it can be beneficialto have the dispersive (neutral) electrode incorporated into thecatheter or another device (instead of placed on the outside of thepatient, as shown in FIG. 47) in order to locate it closer to thetreatment energy delivery body to better localize the energy. This canreduce the risk of causing muscle contractions or arrhythmias, as alower voltage can be applied to generate the same electric field. Theenergy delivery bodies can also be of different sizes in order toenhance the ability to separate the tissue. In some embodiments, theactive portion of the energy delivery body can be that area which is incontact with the airway. It is therefore possible that the area ofcontact for two different energy delivery bodies is nearly the same, forexample, if two similarly-sized energy delivery bodies are placed into asimilarly-sized airway and expanded approximately the same. However, iftwo similarly-sized energy delivery bodies are placed intodifferent-sized airways and/or not expanded the same, the active portionof each energy delivery body can vary significantly. If one electrode isconfigured to have more contact area than the other, a non-uniformelectric field can polarize the cells such that a greater force can begenerated in an effort to separate the tissue. The energy delivery bodycan also be configured to bias the energy field normal to the epitheliumor to create shear along the epithelium.

FIG. 48 depicts an example catheter 102 configured to removably connectto a bronchoscope 112. In this embodiment, a handle 110 of the catheter102 includes a docking mechanism 950 that is removably connectable(e.g., snapped) to an external port 952 of a working channel of thebronchoscope 112. Such a docking mechanism 950 can make it easier forthe operator to control both the bronchoscope 112 and the catheter 102during the procedure. In another embodiment, the handle 110 isconnectable to various bronchoscope attachments and/or accessories(e.g., valve, not shown) that are installable onto the external port 952of the working channel of the bronchoscope 112. In yet anotherembodiment, the handle 110 it does not have any mechanisms that connectsto the external port or valve of the working channel of the bronchoscope112. In such instances, the stability of the catheter 102 is achieved bymeans of friction between the shaft of the catheter 182 and accessories(for example valve) that are installed onto the external port 952 of theworking channel of the bronchoscope 112.

In some embodiments, the length between a distal end 954 of the catheterhandle 110 and the proximal end 956 of the most proximal energy deliverybody 108 is tailored to be substantially equal to the length of theworking channel of the bronchoscope 112, based on the distance betweenthe proximal end of the working channel and the distal end of theworking channel. When the catheter handle 110 is connected (e.g.snapped) to the external port 952 of the working channel of thebronchoscope 112, the energy delivery body or bodies 108 is/areintroduced into the lung passageway. The step of positioning the one ormore energy delivery bodies 108 within the target area of the lungpassageway can be accomplished by moving the bronchoscope 112, andthereby moving the catheter 102 there attached. When the one or moreenergy delivery bodies 108 are successfully positioned within the targetarea and this position is visually assessed and confirmed by theoperator (e.g. using visual bronchoscopy) the one or more energydelivery bodies can be expanded, deployed or otherwise positioned intotissue contact via a mechanism in the catheter handle 110 which isoperatively connected to the one of more energy delivery bodies 108(e.g. lever, slider, plunger, button operatively connected to the one ormore energy delivery bodies 108 (via a pull wire or by other mechanisms)and ready for energy delivery.

In some embodiments, the length between the distal end 954 of thecatheter handle 110 and the distal most distal end 958 of the one ormore energy delivery bodies 108 is tailored to be substantially equal tothe length of the working channel of the bronchoscope 112, based on thedistance between the proximal end of the working channel 954 and thedistal end of the working channel 960. When the catheter handle 110 isconnected (e.g., snapped) to the external port 952 of the bronchoscopeworking channel, the one or more energy delivery bodies 108 are not yetintroduced (FIG. 49A) into the bronchus lumen and are situated withinthe working channel of the bronchoscope 112. The step of introducing theone or more energy delivery bodies 108 into the bronchus lumen (FIG.49B) can be achieved via a primary mechanism of the handle 112 (e.g.lever, slide, plunger, button). When one or more energy delivery bodies108 are successfully positioned within the target area and this positionis visually assessed and confirmed by the operator (e.g. using visualbronchoscopy) the electrodes can be expanded, deployed or otherwisepositioned into tissue contact (FIG. 49C) via a secondary mechanism ofthe handle 112 (e.g. lever, slider, plunger, button) and ready forenergy delivery. In one configuration, a secondary handle mechanism(e.g. lever, slider, plunger, button) is operatively connected (forexample bonded or welded) to the proximal end of the catheter sheath. Todeploy/expand one or more energy delivery bodies 108 the operator wouldmove a secondary mechanism proximally thus moving the catheter sheathproximally which removes the constraint of the one or more energydelivery bodies 108 and allows them to expand. In another configuration,a secondary handle mechanism (e.g. level, slider, plunger, button) isoperatively connected (for example bonded or welded) to the proximal endof the pull or push wire/tubing. To deploy or expand the one or moreenergy delivery bodies 108 the operator would move a secondary mechanismproximally thus pulling the pull wire or tubing or distally thus pushingthe push wire/tubing. In both embodiments depending on the specificconfiguration of the catheter and its deployment mechanism the actionperformed by the operator using a secondary handle mechanism will leadto the deployment or expansion of the one or more energy delivery bodies108. In yet another configuration, there can be more than one secondaryhandle mechanism connected to more than one pull or push wires ortubings. In this scenario the expansion of one or more energy deliverybodies 108 can be controlled independently by activating differentsecondary handle mechanisms at different times and at different levelsof magnitude.

In some embodiments, the length between the distal end of the catheterhandle and the proximal end of the one or more energy delivery bodies108 tailored to be substantially longer that the length of the workingchannel. When one or more energy delivery bodies 108 are introduced intothe lung passageway, the handle is not in contact with the external portof the bronchoscope working channel. The step of positioning one or moreenergy delivery bodies 108 within the target area can be accomplished bymoving the bronchoscope or alternatively moving the catheter itself. Inthis case, the catheter is long enough that the catheter handle can beheld by the operator or set down on or near the patient to allow theoperator to hold the bronchoscope. When one or more energy deliverybodies 108 are successfully positioned within the target area and thisposition is visually assessed and confirmed by the operator (e.g. usingvisual bronchoscopy) the one or more energy delivery bodies 108 can bedeployed or otherwise positioned into tissue contact via a mechanism inthe catheter handle which is operatively connected to the one or moreenergy delivery bodies 108 (e.g. lever, slider, plunger, button) andready for energy delivery.

According to embodiments described herein, which can partially or as awhole combine with other embodiments, the handle of the catheter caninclude a docking mechanism that can be removably connected (e.g.,snapped) onto the external port of the bronchoscope working channel. Inanother embodiment, the handle can be connected to the variousattachments and/or accessories (e.g., valve) that are installed onto theexternal port of the bronchoscope working channel. In yet anotherembodiment, the handle may not have any mechanisms that snap onto theexternal port of the bronchoscope working channel and the stability ofthe device is achieved by means of friction between the shaft of thecatheter and accessories (e.g., valve) that are installed onto theexternal port of the bronchoscope working channel.

VIII. Treatment Patterns

It may be appreciated that a patient P may possess a single target zonefor treatment or multiple target zones. A target zone is a contiguousarea of a lung passageway that is targeted for treatment. A single lungpassageway may include multiple target zones. Likewise, target zones maybe located along separate lung passageways. Each target zone may includeone or more target segments. A target segment is a portion of the lungpassageway that is treatable by a single placement of the catheter 102(i.e. single treatment). Thus, the target segment is defined by theouter area borders along the long airway wall W within which the walltissue has been treated by the one or more electrodes 108 of thecatheter 102. It may be appreciated that different embodiments of thecatheter 102 may cover differing sized areas of a lung passageway. Thus,the size of a target segment may vary based on catheter 102/system 100design. In addition, the catheter 102 may be sequentially moved along alung passageway to create multiple adjacent target segments, whereinadjacent target segments cover the target zone.

Thus, methods for treating the airway of a patient can include: (a)performing a single treatment at a target segment, (b) performing two ormore treatments at adjacent target segments such that the overalltreatment zone is generally continuous, and/or (c) performing two ormore treatments spaced apart from one another. FIG. 50 is a schematicillustration of a single target segment 1000 within a mainstem bronchiMB of a lung. In this embodiment, the target segment 1000 is treated byplacement of the one or more energy delivery bodies 108 of the catheter102 and delivery of treatment energy thereto. FIG. 51 is a schematicillustration of two target segments 1000 a, 1000 b positioned adjacentto each other such that the overall target or treatment zone 1002 isgenerally contiguous. Typically, the two target segments 1000 a, 1000 bare treated by first positioning the catheter 102 so as to treat thefirst target segment 1000 a, then repositioning the catheter 102 so asto treat the second target segment 1000 b. It may be appreciated thatthe various target segments may alternatively be treated with differentcatheters 102. It may also be appreciated that the target segments 1000a, 1000 b may be treated in any order. Likewise, in some embodiments,target segments overlap. Thus, both FIGS. 50-52 illustrate a singletarget zone within a lung passageway. FIG. 52 is a schematicillustration of two target zones 1004, 1006 within a patient. In thisembodiment, a first target zone 1004 is disposed within a mainstembronchi MB and a second target zone 1006 is disposed within a lobarbronchi LB of lung. Here, the first target zone 1004 is covered by atarget segment 1008 and the second target zone 1006 is covered by atarget segment 1010 wherein the target segments 1008, 1010 are spaceapart from one another. Again, the two target segments 1008, 1010 may betreated by first positioning the catheter 102 so as to treat the firsttarget segment 1008, then repositioning the catheter 102 so as to treatthe second target segment 1010. It may be appreciated that the varioustarget segments may alternatively be treated with different catheters102. It may also be appreciated that the target segments 1008, 1010 maybe treated in any order. It is understood that these figures provideexample treatment patterns that can be used solely or in combinationwith one another to yield the desired outcome.

It may also be appreciated that within a target segment, the lungpassageway tissue may receive a variety of treatment patterns at anygiven cross-section. For example, some embodiments include treating thefull circumference of the airway over a given length of the targetsegment and other embodiments include treating one or multiple discreteportions of the circumference of the airway over a given length of thetarget segment.

FIG. 53 is a schematic side view illustration of a portion of an energydelivery body 108 comprised of a braided basket. The braid is comprisedof individual wires 120 which deliver energy. Between the wires arepores 1050. Depending on the degree of expansion (indicated by diameter1052), the pore size will vary. FIG. 54 is a schematic cross-sectionalview of the energy delivery body 108 of FIG. 53 positioned within a lungpassageway having an airway wall W. Thus, the energy delivery body 108is illustrated as a plurality of cross-sections of the wires 120disposed against the inner lumen of the lung passageway (i.e. along theinner surface of the airway wall W). In some embodiments, treatment of acontinuous full circumference (shading, 1054) of the airway W isachieved. Likewise, in some embodiments, continuous full circumferencetreatment along a length 1056 of the energy delivery body 108 is alsoachieved. This effect is illustrated in FIG. 55.

In some embodiments, in order to achieve substantially continuous, fullcircumference treatment over a given length, at least the appliedelectric field (V/cm) and the electrode design are taken intoconsideration. In one example, the electric field is applied in amonopolar fashion, wherein the field is applied to substantially theenergy delivery body 108, and a dispersive (neutral) electrode ispositioned either on the exterior of the patient or elsewhere within thebody. The change and/or distribution of the magnitude of the field willdepend on the applied voltage and the geometric relationship of thewires 120. In the example provided in FIGS. 53-55, the energy deliverybody 108 in contact with the circumference and length of tissue to betreated is constructed from a metallic braid of wires 120. By havingmany wires 120 close together, the field between each wire 120 can besufficient to cause the desired tissue effects continuously around theentire circumferential area of contact 1054. In this example, thediameter 1052 is designed to expand from approximately 2-3 mm indiameter when fully collapsed for delivery to about 10 mm, 12 mm, 15 mm,18 mm, 20 mm, or 22 mm in diameter when fully expanded, including allvalues and subranges in between. Depending on the degree of expansion,the pore 1050 size will vary, but will generally be effective atgenerating a continuous tissue effect with pore sizes up at least 10mm². If the pore size becomes significantly larger, the same fieldapplied can result in a discontinuous tissue effect (indicated byshading 1056), as depicted in FIG. 56. In this embodiment, the energydelivery body is comprised of four wires 120, wherein each wire 120provides a tissue effect contributing to an overall discontinuous tissueeffect. This can increase the speed of healing while still affecting asufficient amount of tissue to provide a clinical benefit. Adiscontinuous lesion can also be achieved by reducing the appliedelectric field.

It may be appreciated that some embodiments have energy delivery bodieswhich include treating portions of the circumference ranging from about25 to about 50%, from about 50% to about 75%, or from about 75% to about100%, including all values and subranges in between. Some embodimentsinclude treating lengths ranging from about 5 mm to about 20 mm,including all values and subranges in between, allowing for sufficientflexibility to treat a wide range of patient anatomies while minimizingthe number of individual treatments to be performed.

IX. General Embodiments

In some embodiments described herein, which can partially or as a wholebe combined with other embodiments, a pulmonary tissue modificationsystem for performing a pulmonary procedure can include an energyproducing generator, an energy deliver catheter, accessories, and one ormore imaging modalities.

In some embodiments, a bipolar catheter with two energy delivery bodiesmounted near the distal end is connected to an energy producinggenerator outside of the body. The distal end of the catheter is passedthrough the mouth or nose and into the bronchial tree using abronchoscope or other direct visualization system. The energy deliverybodies are deployed, expanded and/or otherwise positioned such that theycontact the airway wall. The operator can then activate the generatorvia any suitable interface such as, for example, a foot switch, a buttonon the generator, a button on the catheter, or remote control, todeliver energy to airway tissue adjacent to and/or between theelectrodes. In some embodiments, the operator can move the energydelivery bodies to another section of the diseased airway to deliveranother treatment, or elect to treat the entire surface of a section ofthe airway, or multiple sections of the airways. In some embodiments,more than one treatment can be applied to the same portion of theairway, depending on the desired depth of penetration. In someembodiments, two or more different energy delivery algorithms can beemployed to affect the depth of penetration.

In some embodiments, a monopolar catheter, with a single energy deliverybody mounted near the distal end, is connected to an energy producinggenerator outside of the body. The distal end of the catheter is passedthrough the mouth or nose and into the bronchial tree using abronchoscope or other direct visualization system. The electrode isdeployed, expanded and/or otherwise positioned such that it contacts theairway wall. A dispersive (neutral) or return electrode is affixed toanother surface of the patient (e.g., an external location, such as thepatient's skin), and is also connected to the electrical generator. Theoperator can then activate the generator via, for example, a footswitch, a button on the generator, a button on the catheter, or remotecontrol to deliver energy to airway tissue via the electrode. Theoperator can move the energy delivery body to another section of thediseased airway to deliver a treatment, or elect to treat the entiresurface of a section of the airway, or multiple sections of the airways.In some embodiments, two or more monopolar energy delivery bodies can beincorporated into one or more catheters to enable treatment of multiplelocations without repositioning the catheter(s). More than one treatmentcan be applied to the same portion of the airway, depending on thedesired depth of penetration. In some, embodiments, two or moredifferent energy delivery algorithms can be employed to affect the depthof penetration. In some embodiments, a user interface on the generatorcan be used to select the desired treatment algorithm, while in otherembodiments, the algorithm can be automatically selected by thegenerator based upon information obtained by one or more sensors.

In some embodiments, a catheter with a plurality of energy deliverybodies mounted near the distal end is connected to an energy producinggenerator outside of the body. The distal end of the catheter is passedthrough the mouth or nose and into the bronchial tree using abronchoscope or other direct visualization system. The energy deliverybodies are deployed, expanded, or otherwise positioned such that theycontact the airway wall. The operator can then activate the generatorvia, for example, a foot switch, a button on the generator, a button onthe catheter, or remote control to deliver energy to airway tissue viathe energy delivery bodies. In some embodiments, the energy delivery canbe multiplexed across any one or more of the energy delivery bodies inany suitable pattern to affect the desired target tissue. In someembodiments, a dispersive (neutral) electrode can be affixed to anothersurface of the patient, such as the patient's skin, and also connectedto the electrical generator to allow for monopolar energy delivery toany of the energy delivery bodies. More than one treatment can beapplied to the same portion of the airway, depending on the desireddepth of penetration. In some embodiments, two or more different energydelivery algorithms can be employed to affect the depth of penetration.The user interface on the generator can be used to select the desiredtreatment algorithm, or the algorithm can be automatically selected bythe generator based upon information

In some embodiments, the targeted treatment area can be identified andused to select a treatment algorithm sufficient to affect the pathogeniccells and/or deeper tissues. The electrode system can then be deployedat the site of pathogenic cells and/or abnormal airway wall tissue andenergy delivered to affect the target tissue. The imaging modality (ormodalities) can be used before, during, between, and/or aftertreatment(s) to determine where treatment(s) have or have not beendelivered and/or whether the energy adequately affected the airway wall.If it is determined that a target treatment area was missed or that atarget treatment area was not adequately affected, the energy deliverycan be repeated followed by imaging as described herein until adequatetreatment is achieved. Further, the imaging information can be utilizedto determine if specific cell types and or a desired depth of therapywas applied. This can allow for customization of the energy deliveryalgorithm for treating a wide variety of patient anatomies.

In some embodiments, any of the apparatuses and/or systems describedherein can be used in methods for treating diseased airways, and/orother lung tissue (e.g., parenchyma), which can generally includeaccessing the airway, and optionally performing pre-, intra-, and/orpost-procedural imaging to plan, guide and/or verify treatment. In someembodiments, the methods can further include one or more of treating asufficient treatment zone with each energy application, treating asufficient overall treatment area, treating to a sufficient depth,treating a pre-defined cell type or types, customizing therapy based onimaging and/or sensor information, and combinations thereof.

X. EXAMPLES

The following examples further illustrate embodiments of the systems andmethods disclosed herein, and should not be construed in any way aslimiting their scope.

Example 1: Circumferential Treatment and Tissue Effect With a BipolarSystem

A non-thermal energy delivery apparatus having bipolar expandable energydelivery bodies was developed. The apparatus included two energydelivery bodies, each comprised of nitinol, braided, expandingelectrodes mounted concentrically on a catheter shaft with a mechanismto expanded and contract both energy delivery bodies (e.g., see FIG.27). The expanded energy delivery body diameters ranged from about 5 mmto about 20 mm. There energy delivery bodies were substantially equal inlength at about 3 cm each, and were spaced along the longitudinal axisof the catheter shaft about 2.5 cm apart from edge to edge. To evaluatethe effect of pulsed high-voltage energy on epithelial and submucosaltissue layers within the airway, the apparatus was introduced into theleft and/or right bronchi of live, anesthetized pigs and energy wasdelivered in the form of bipolar, square-wave pulses at a pulsefrequency of about 300 kHz, pulse amplitude of about 4000 V, and totalenergy delivery duration of about 415 microseconds (83 microseconds perpacket, 5 packets).

Following the procedure, the animals were recovered, then subsequentlyeuthanized after approximately twenty-four hours. The airways were thendissected out and fixed in formalin for about forty-eight hours. Theairways were then sectioned at approximately 5 mm increments andprocessed for histology in typical fashion. Sections of both treated anduntreated areas were processed for comparison purposes. Slides wereprepared using a hematoxylin and eosin (H&E) stain.

FIG. 57A shows it typical section of healthy, untreated airway, and FIG.57B shows a typical section of treated airway, 24 hrs post energydelivery. In the untreated airway (FIG. 57A), ciliated epithelium E withpseudostratified columnar epithelial cells PCEC and goblet cells GC andintact submucosal structures, including submucosal glands SG, connectivetissue CT, smooth muscle SM, and cartilage CL can be observed. In thetreated airway (FIG. 57B, epithelial E with pseudostratified columnarepithelial cells PCEC and goblet cells GC have been substantiallyremoved or destroyed, leaving only cellular remnants and the basementmembrane. Further, the submucosal structures have been affected; mostnotably, submucosal gland cells SG are mostly absent, and extra-cellulargland structures have been disrupted. Smooth muscle SM and connectivetissue layers CT also show signs of cellular damage and disruption whilethe cartilage CL was left unaffected.

Example 2: Circumferential Treatment and Tissue Effect With a MonopolarSystem

A non-thermal energy delivery apparatus having a monopolar expandableenergy delivery body was developed. The apparatus included a singleenergy delivery body comprised of nitinol, braided, expanding electrodemounted concentrically on a catheter shaft with a mechanism to expandedand contract the energy delivery body (e.g., see FIG. 26). The expandedenergy delivery diameter ranged from about 5 mm to about 20 mm. Toevaluate the effect of pulsed high-voltage energy on epithelial andsubmucosal tissue layers within the airway, the apparatus was introducedinto the left and/or right bronchi of live, anesthetized pigs and energywas delivered in the form of bipolar, square-wave pulses at a pulsefrequency of 300 kHz, pulse amplitude of 4000 V and total energydelivery duration of 415 microseconds (83 microseconds per packet, 5packets).

Following the procedure, the animals were recovered, then subsequentlyeuthanized after approximately twenty-four hours. The airways thendissected out and fixed in formalin for about forty-eight hours. Theairways were then sectioned at approximately 5 mm increments andprocessed for histology in typical fashion. Sections of both treated anduntreated areas were processed for comparison purposes. Slides wereprepared using a hematoxylin and cosin (H&E) stain.

FIG. 58A shows a typical section of healthy, untreated airway and FIG.58B shows a typical section of treated airway 24 hrs post energydelivery. In the untreated airway (FIG. 58A), ciliated epithelium E withpseudostratified columnar epithelial cells PCEC and goblet cells GC andintact submucosal structures, including submucosal glands SG, connectivetissue CT, cartilage CL and smooth muscle SM can be observed. In thetreated airway (FIG. 58B) epithelial E and goblet cells GC have beensubstantially removed or destroyed, leaving only cellular remnants andthe basement membrane BM. Further, the submucosal structures have beenaffected; most notably, submucosal gland cells SG are absent in somelocations. In this example, extra-cellular gland structures, includingsmooth muscle SM and connective tissue layers CT have been left largelyunaffected. The cartilage CL was left unaffected. The treatment affectsare similar using either the bipolar or monopolar systems, with tissuechanges noted where the electrode is in contact with the airway.

As used herein, the terms “about” and/or “approximately” when used inconjunction with numerical values and/or ranges generally refer to thosenumerical values and/or ranges near to a recited numerical value and/orrange. In some instances, the terms “about” and “approximately” can meanwithin ±10% of the recited value. For example, in some instances, “about100 [units]” can mean within ±10% of 100 (e.g., from 90 to 110). Theterms “about” and “approximately” can be used interchangeably.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A system for treating a wall of a lung passagewayof a patient comprising: a catheter comprising at least one electrodedisposed near its distal end, wherein the at least one electrode isconfigured to be positioned within a lumen of the lung passageway sothat the at least one electrode is able to transmit energy toward thewall of the lung passageway; and a generator in electrical communicationwith the at least one electrode, wherein the generator includes at leastone energy delivery algorithm configured to provide an electric signalto the at least one electrode causing the energy to be transmitted to atargeted cell depth not extending beyond a basement membrane of the wallfrom the at least one electrode for a treatment duration so as toprovide a treatment of a condition of the lung passageway, wherein theelectric signal comprises distinct energy packets wherein each energypacket comprises a series of biphasic pulses.
 2. A system as in claim 1,wherein the energy is below a threshold for thermal ablation of the wallof the lung passageway throughout the duration of treatment.
 3. A systemas in claim 1, wherein each distinct packet has a cycle count of up to60 biphasic pulses.
 4. A system as in claim 1, wherein each distinctenergy packet has a duration of up to 100 microseconds.
 5. A system asin claim 4, wherein the electric signal comprises five distinct energypackets and wherein each energy packet has a duration of 100microseconds.
 6. A system as in claim 1, wherein the treatment comprisesselectively removing or killing cells of the wall of the lung passagewayassociated with the condition.
 7. A system as in claim 1, wherein thetreatment comprises selectively modifying cells of the wall of the lungpassageway associated with the condition.
 8. A system as in claim 1,wherein the treatment selectively targets endothelial cells,pseudostratified columnar epithelial cells, goblet cells, and/or basalcells.
 9. A system as in claim 1, wherein the at least one energydelivery algorithm is configured to provide an electric signal to the atleast one electrode causing the energy to be transmitted from the atleast one electrode toward and not beyond an epithelial layer.
 10. Asystem as in claim 1, further comprising a return electrode wherein thesystem is configured to provide the electric signal of the energy to thepatient in a monopolar fashion with the use of the return electrode. 11.A system as in claim 10, wherein each pulse of the series of biphasicpulses is between approximately 1000-2500 volts.
 12. A system as inclaim 1, wherein the at least one electrode comprises at least onebipolar electrode pair and wherein the generator is in electricalcommunication with the at least one bipolar electrode pair so as toprovide the electric signal to the at least one bipolar electrode paircausing the energy to be transmitted to the wall of the lung passagewayin a bipolar fashion.
 13. A system as in claim 12, wherein each pulse ofthe series of biphasic pulses is between approximately 100-1900 volts.14. A system as in claim 1, wherein at least one of the at least oneelectrode comprises a plurality of wires forming an expandable basketconfigured to expand within the lung passageway.
 15. A system as inclaim 1, wherein at least one of the at least one electrode comprises anenergy delivery body having a plurality of separate active areas whichare each insulated from each other.
 16. A system as in claim 1, whereinthe at least one of the at least one electrode comprises an energydelivery body having an active area isolated from a remainder of theenergy delivery body.
 17. A system as in claim 1, wherein the generatorcomprises a processor in communication with at least one sensor, whereinthe processor modifies at least one of the at least one energy deliveryalgorithm based on data from the at least one sensor.
 18. A system as inclaim 2, wherein the threshold for thermal ablation is 65 degreesCelsius.
 19. A system as in claim 1, wherein the at least one energydelivery algorithm is configured to provide an electric signal to the atleast one electrode causing the energy to be transmitted from the atleast one electrode to a mucus layer.
 20. A system as in claim 1,wherein the treatment comprises selectively removing or killing one ormore pathogens.
 21. A system as in claim 1, wherein each distinct energypacket has a frequency of 500-800 kHz.
 22. A system as in claim 17,wherein the at least one sensor comprises a temperature sensor andwherein the generator modifies at least one of the at least one energydelivery algorithm based on temperature data from the temperature sensorso as to maintain temperature at or below 65 degrees Celsius.